Cyclopentanperhydrophenanthren-17β-(3-furyl)-3-derivatives and pharmaceutical compositions comprising same for the treatment of cardiovascular disorders

ABSTRACT

Cyclopentanperhydrophenantren-17β-(3-furyl)-3-derivatives and pharmaceutical compositions containing same for the treatment of cardiovascular disorders such as heart failure and hypertension, are disclosed.

The present invention relates tocyclopentanperhydrophenanthren-17β-(3-furyl)-3-derivatives, a processfor their preparation and pharmaceutical compositions containing samefor the treatment of cardiovascular disorders such as heart failure andhypertension.

The compounds have formula (I): ##STR1##

wherein:

X is O or S;

the symbol means that the substituents in positions 3, 5, 14, and 15 canhave an α or β configuration, with the proviso that when X═S only the 3βconfiguration is present;

the symbol --- means that single or double bonds can be present;

R is C2-C6 alkyl or C3-C5 alkenyl, substituted independently by aquaternary ammonium group or 2-(2-imidazolinyl) or one or more OR3, SR3,NR4R5, C(NH)NR6R7, with the proviso that when X is oxygen and R1 is [3OHand R2 is H and the configuration in position 5 is α and C2-C6 alkyl isethyl or n-propyl, NR4R5 is not dimethylamino or morpholino;

R1 is H or hydroxy or methoxy or O(CH₂)_(n) NR8R9; wherein n is 2 or 3;

R2 is H or R1 and R2 taken together form an oxirane ring;

R3 is C2-C4 alkyl substituted by one or more NR6R7 or by NR6R7 and OH;

R4, R5 are independently H, methyl, C2-C6 alkyl or C3-C6 alkenylunsubstituted or substituted by an oxirane or by one or more NR6R7, orNR6R7 and OH, or R4 and R5 taken together with the nitrogen atom form anunsubstituted or substituted, saturated or unsaturated penta- orhexa-monoheterocyclic ring optionally containing another heteroatomchosen from oxygen, sulphur or nitrogen, or R4 is hydrogen and R5 isC(NH)NH2;

R6, R7 are independently H, C1-C4 alkyl, or R6 and R7 taken togetherwith the nitrogen atom form a saturated or unsaturated penta- orhexa-monoheterocyclic ring optionally containing another heteroatomchosen from oxygen, sulphur or nitrogen;

R8, R9 are independently H, methyl, ethyl or R8 and R9 taken togetherwith the nitrogen atom form a saturated or unsaturated penta- orhexa-monoheterocyclic ring optionally containing another heteroatomchosen from oxygen, sulphur or nitrogen.

The invention includes within its scope all the possible stereoisomers,in particular Z and E isomers, optical isomers and their mixtures andthe metabolites and the metabolic precursors of the compounds of formula(I).

Pharmaceutically acceptable salts of (I) are salts which retain thebiologically activity of the base and are derived from such known acidspharmacologically acceptable such as e.g. hydrochloric, sulfuric,phosphoric, malic, tartaric, maleic, citric, methane-sulfonic or benzoicacid.

The alkyl and alkenyl groups may be branched or straight chain groups

The C2-C6 alkyl group is preferably a C2-C4 alkyl group, e.g. methyl,ethyl, propyl, isopropyl, butyl, sec-butyl.

The C3-C6 alkenyl group is preferably a C3-C4 alkenyl group.

The quaternary ammonium group is preferably a trimethylammonium- or aN-methylpyrrolidinium- or a N-methyl-piperidinium- group.

The OR3 group is preferably 2-aminoethoxy, 3-aminopropoxy,2-dimethylaminoethoxy, 3-dimethylaminopropoxy, 3-amino-2-hydroxypropoxy,2,3-diaminopropoxy, 2-(1-pyrrolidinyl)ethoxy, 3-(1-pyrrolidinyl)propoxy.

The SR3 group is preferably 2-aminoethylthio, 3-aminopropylthio,2-dimethylaminoethylthio, 3-dimethylaminopropylthio,3-amino-2-hydroxypropylthio, 2,3-diaminopropylthio,2-(1-pyrrolidinyl)ethylthio, 3-(1-pyrrolidinyl)propylthio.

The NR4R5 group is preferably amino, methylamino, ethylamino,propylamino, isopropylamino, allylamino, propargylamino, dimethylamino,pyrrolidinyl, morpholino, piperazinyl, imidazolyl, guanidino,2-aminoethylamino, 3-aminopropylamino, 2-(1-pyrrolidinyl)ethylamino,3-(1-pyrrolidinyl)propylamino, 3-amino-2-hydroxypropylamino,3-(1-pyrrolidinyl)2-hydroxypropylamino, 2,3-diaminopropylamino,(2-(1-pyrrolidinyl)ethyl)methylamino.

The C(NH)NR6R7 group is preferably a primary amidino group.

Preferred examples of specific compounds according to the presentinvention are:

3β-(2-Trimethylammonium-ethoxy)-17β-(3-furyl)-5β-androstan-14β-olchloride

3β-(2-(N-Methyl-1-pyrrolydinium)ethoxy)-17β-(3-furyl)-5β-androstan-14β-oliodide

3β-(2-Aminoethoxy)-17β-(3-furyl)-5β-androstan-14β-ol

3β-(3-Aminopropoxy)-17β-(3-furyl)-5β-androstan-14β-ol

3β-(4-Aminobutoxy)-17β-(3-furyl)-5β-androstan-14β-ol

3β-(4-Aminobut-(2-en)oxy)-17β-(3-furyl)-5β-androstan-14.beta.-ol

3β-(4-Aminobut-(2-en)oxy)-17β-(3-furyl)-5β-androstan-14.beta.-ol

3β-(2-Methylaminoethoxy)-17β-(3-furyl)-5β-androstan-14β-ol

3β-(2-(1-Pyrrolidinyl)ethoxy)-17β-(3-furyl)-5β-androstan-14.beta.-ol

3β-(3-(1-Pyrrolidinyl)propoxy)-17β-(3-furyl)-5β-androstan-14β-ol

3β-(2-(1-Piperazinyl)ethoxy)-17β-(3-furyl)-5β-androstan-14.beta.-ol

3β-(3-(1 -Piperazinyl )propoxy)-17β-(3-furyl )-5β-androstan-14β-ol

3β-(2-(1-Imidazolyl)ethoxy)-17β-(3-furyl)-5β-androstan-14.beta.-ol

3β-(2-(2-Imidazolin-2-yl)ethoxy)-17β-(3-furyl)-5β-androstan-14β-ol

3β-(2-(2-Amidino)ethoxy)-17β-(3-furyl)-5β-androstan-14β-ol

3β-(2-(2-Aminoethoxy)ethoxy)-17β-(3-furyl)-5β-androstan-14.beta.-ol

3β-(2-(3-Aminopropoxy)ethoxy)-17β-(3-furyl)-5β-androstan-14.beta.-ol

3β-(2-(2-(1-Pyrrolidinyl)ethoxy)ethoxy)-17β-(3-furyl)-5β-androstan-14β-ol.

3β-(2-(2-(1-Pyrrolidinyl)ethylthio)ethoxy)-17β-(3-furyl)-5β-androstan-14β-ol

3β-(2-(2-(1-Pyrrolidinyl)ethylamino)ethoxy)-17β-(3-furyl)-5β-androstan-14β-ol

3β-(2-(3-Dimethylaminopropoxy)ethoxy)-17β-(3-furyl)-5β-androstan-14β-ol

3β-(2-(3-Dimethylaminopropylthio)ethoxy)-17β-(3-furyl)-5β-androstan-14β-ol

3β-(2-(3-Dimethylaminopropylamino)ethoxy)-17β-(3-furyl)-5β-androstan-14β-ol

3β-(2-(3-(1-Pyrrolidinyl)propoxy)ethoxy)-17β-(3-furyl)-5β-androstan-14β-ol

3β-(2-(3-(1-Pyrrolidinyl)propylamino)ethoxy)-17β-(3-furyl)-5.beta.-androstan-14β-ol

3β-(2-(3-Amino-2-hydroxypropoxy)ethoxy)-17β-(3-furyl)-5β-androstan-14β-ol

3β-(2-(2,3-Diaminopropoxy)ethoxy)-17β-(3-furyl)-5β-androstan-14β-ol

3β-(2,3-Bis(1-pyrrolidinyl)propoxy)-17β-(3- furyl)-5β-androstan-14β-ol

3β-(2-Guanidinoethoxy)-17β-(3-furyl)-5β-androstan-14β-ol

3β-(3-Guanidinopropoxy)-17β-(3-furyl)-5β-androstan-14β-ol

3β-(4-Guanidinobutoxy)-17β-(3β-furyl)-5β-androstan-14.beta.-ol

3β-(2,3-Diaminopropoxy)-17β-(3-furyl)-5β-androstan-14β-ol

3β-(3-(3-Amino-2-hydroxypropoxy)propoxy)-17β-(3-furyl)-5β-androstan-14β-ol

3β-(3-(3-Amino-2-hydroxypropylamino)propoxy)-17β-(3-furyl)-5.beta.-androstan-14β-ol

3β,14β-Bis(2-(1-pyrrolidinyl)ethoxy)-17β-(3-furyl)-5β-androstane

3β,14β-Bis(3-(1-pyrrolidinyl)propoxy)-17β-(3-furyl)-5β-androstane

3β-(3-Aminopropoxy)-14β-methoxy-17β-(3-furyl)-5β-androstane

3β-(2-(1-Pyrrolydinyl)ethoxy)-14β-methoxy-17β-(3-furyl)-5.beta.-androstane

3β-(3-(1-Pyrrolidinyl)propoxy)-14β-methoxy-17β-(3-furyl)-5.beta.-androstane

3β-(2-(2-(1-Pyrrolidinyl)ethoxy)ethoxy)-14β-methoxy-17β-(3-furyl)-5β-androstane

3β-(3-Aminopropoxy)-17β-(3-furyl)-androst-4-en-14β-ol

3β-(2-(1-Pyrrolidinyl)ethoxy)-17β-(3-furyl)-androst-4-en-14β-ol

3β-(3-(1 -Pyrrolidinyl)propoxy)-17β-(3-furyl)-androst-4-en-14β-ol

-(2-(2-(1-Pyrrolidinyl)ethoxy)ethoxy)-17β-(3-furyl)-androst-4-en-14.beta.-ol

3β-(3-Aminopropoxy)-17β-(3-furyl)-androst-5-en-14β-ol

3β-(2-(1-Pyrrolidinyl)ethoxy)-17β-(3-furyl)-androst-5-en-14β-ol

3β-(3-(1-Pyrrolidinyl)propoxy)-17β-(3-furyl)-androst-5-en-14.beta.-ol

3β-(2-(2-(1-Pyrrolidinyl)ethoxy)ethoxy)-17β-(3-furyl)-androst-5-en-14β-ol

3β-(3-Aminopropoxy)-17β-(3-furyl)-5α-androstan-14β-ol

3β-(2-(1-Pyrrolidinyl)ethoxy)-17β-(3-furyl)-5α-androstan-14β-ol

3β-(3-(1-Pyrrolidinyl)propoxy)-17β-(3-furyl)-5α-androstan-14β-ol

3β-(2-(2-(1-Pyrrolidinyl)ethoxy)ethoxy)-17β-(3-furyl)-5α-androstan-14β-ol

3β-(3-Aminopropoxy)-17β-(3-furyl)-5β-androstan-14α-ol

3β-(2-(1-Pyrrolidinyl)ethoxy)-17β-(3-furyl)-5β-androstan-14.alpha.-ol

3β-(3-(1-Pyrrolidinyl)propoxy)-17β-(3-furyl)-5β-androstan-14α-ol

3β-(2-(2-(1-Pyrrolidinyl)ethoxy)ethoxy)-17β-(3-furyl)-5β-androstan-14α-ol

3β-(3-Aminopropoxy)-14β,15β-epoxy-17β-(3-furyl)-5β-androstane

3β-(2-(1-Pyrrolidinyl)ethoxy)-14β,15β-epoxy-17β-(3-furyl)-5β-androstane

3β-(3-(1-Pyrrolidinyl)propoxy)-14β,15β-epoxy-17β-(3-furyl)-5β-androstane

3β-(2-(2-(1-Pyrrolidinyl)ethoxy)ethoxy)-14β,15β-epoxy-17.beta.-(3-furyl)-5β-androstane

3β-(3-Aminopropoxy)-14β,15β-epoxy-17β-(3-furyl)-androst-4-ene

3β-(2-(1-Pyrrolidinyl)ethoxy)-14β,15β-epoxy-17β-(3-furyl)-androst-4-ene

3β-(3-(1-Pyrrolidinyl)propoxy)-14β,15β-epoxy-17β-(3-furyl)-androst-4-ene

3β-(2-(2-(1-Pyrrolidinyl)ethoxy)ethoxy)-14β,15β-epoxy-17.beta.-(3-furyl)-androst-4-ene

3β-(3- Aminopropoxy)-14β,15β-epoxy-17β-(3-furyl)-androst-5-ene

3β-(2-(1-Pyrrolidinyl)ethoxy)-14β,15β-epoxy-17β-(3-furyl)-androst-5-ene

3β-(3-(1-Pyrrolidinyl)propoxy)-14β,15β-epoxy-17β-(3-furyl)-androst-5-ene

3β-(2-(2-(1-Pyrrolidinyl)ethoxy)ethoxy)-14β,15β-epoxy-17.beta.-(3-furyl)-androst-5-ene

3β-(3-Aminopropoxy)-14β,15β-epoxy-17β-(3-furyl)-5.alpha.-androstane

3β-(2-(1-Pyrrolidinyl)ethoxy)-14β,15β-epoxy-17β-(3-furyl)-5α-androstane

3β-(3-(1-Pyrrolidinyl)propoxy)-14β,15β-epoxy-17β-(3-furyl)-5α-androstane

3β-(2-(2-(1-Pyrrolidinyl)ethoxy)ethoxy)-14β,15β-epoxy-17.beta.-(3-furyl)-5α-androstane

3β-(3-Aminopropoxy)-14α,15α-epoxy-17β-(3-furyl)-5.beta.-androstane

3β-(2-(1-Pyrrolidinyl)ethoxy)-14α,15α-epoxy-17β-(3-furyl)-5β-androstane

3β-(3-(1-Pyrrolidinyl)propoxy)-14α,15α-epoxy-17β-(3-furyl)-5β-androstane

3β-(2-(2-(1-Pyrrolidinyl)ethoxy)ethoxy)-14α,15α-epoxy-17.beta.-(3-furyl)-5β-androstane

3β-(3-Aminopropoxy)-17β-(3-furyl)-5β,14β-androstane

3β-(2-(1-Pyrrolidinyl)ethoxy)-17β-(3-furyl)-5β,14β-androstane

3β-(3-(1-Pyrrolidinyl)propoxy)-17β-(3-furyl)-5β,14β-androstane

3β-(2-(2-(1-Pyrrolidinyl)ethoxy)ethoxy)-17β-(3-furyl)-5β,14.beta.-androstane

3β-(3-Aminopropoxy)-17β-(3-furyl)-androst-4-ene

3β-(2-(1-Pyrrolidinyl)ethoxy)-17β-(3-furyl)-androst-4-ene

3β-(3-(1-Pyrrolidinyl)propoxy)-17β-(3-furyl)-androst-4-ene

3β-(2-(2-(1-Pyrrolidinyl)ethoxy)ethoxy)-17β-(3-furyl)-androst-4-ene

3β-(3- Aminopropoxy)-17β-(3-furyl)-androst-5-ene

3β-(2-(1-Pyrrolidinyl)ethoxy)-17β-(3-furyl)-androst-5-ene

3β-(3-(1-Pyrrolidinyl)propoxy)-17β-(3-furyl)-androst-5-ene

3β-(2-(2-(1-Pyrrolidinyl)ethoxy)ethoxy)-17β-(3-furyl)-androst-5-ene

3β-(3-Aminopropoxy)-17β-(3-furyl)-5α-androstane

3β-(2-(1-Pyrrolidinyl)ethoxy)-17β-(3-furyl)-5α-androstane

3β-(3-(1-Pyrrolidinyl)propoxy)-17β-(3-furyl)-5α-androstane

3-(2-(2-(1-Pyrrolidinyl)ethoxy)ethoxy)-17β-(3-furyl)-5α-androstane

3-(3-Aminopropoxy)-17β-(3-furyl)-5β-androstane

3-(2-(1-Pyrrolidinyl)ethoxy)-17β-(3-furyl)-5β-androstane

3β-(3-(1-Pyrrolidinyl)propoxy)-17β-(3-furyl)-5β-androstane

3β-(2-(2-(1-Pyrrolidinyl)ethoxy)ethoxy)-17β-(3-furyl)-5β-androstane

3-(2-(4-Morpholinoethylthio)-17β-(3-furyl)-5β-androstan-14β-ol

and the corresponding X═S derivatives and for X═O the corresponding 3αderivatives.

The starting materials for preparing the compounds of formula (I),wherein X═O, R1 and R2 are as above defined, are compounds of formula(II), wherein X═O, R1 is hydrogen or hydroxy and R2 is H, or R1 and R2taken together form an oxirane ring, which are known compounds such as,for example, 17β-(3-furyl)-5α-androstan-3β-ol,17β-(3-furyl)-5β-androstan-3β-ol (U.S. Pat. No. 3,436,390),17β-(3-furyl)-5β-androstane-3β,14β-diol (Minato H. and Nagasaki T., J.Chem. Soc.(C), 1966, 377), 17β-(3-furyl)-5β-androstane-3α,14β-diol(Humber D. et al., Steroids, 1983, 42,189),14β,15β-epoxy-17β-(3-furyl)-5β-androstan-3β-ol (Yoshii E. et al., Chem.Pharm. Bull., 1976, 24, 3216) or are prepared from the known compoundswith methods well known to those skilled in the art. ##STR2##

For instance, the compounds of formula (II), wherein X═O, R1 is hydrogenor hydroxy, R2 is H or R1 and R2 taken together form an oxirane ring,can be obtained from known 3-oxo derivatives (III), wherein R1 ishydrogen or hydroxy, R2 is H or R1 and R2 taken together form an oxiranering, such as, e.g. 14β-hydroxy-17β-(3-furyl)-androst-4-en-3-one (GB.Pat. 1081647), 17β-(3-furyl)-androst-4-en-3-one,17β-(3-furyl)-5α-androstan-3-one (U.S. Pat. No. 3436390), by reductionwith complex hydrides, e.g. NaBH₄ or LiAlH₄ ortri-tert-butoxyaluminum-hydride, the 3α or 3β isomer depending on thereducing reagent. ##STR3##

Alternatively, the compounds of formula (II), wherein X═O, R1 is H orhydroxy, R2 is H or R1 and R2 taken together form an oxirane ring, canbe obtained from known 17β-lactones of 3α or 3β hydroxy derivatives(IV), wherein R1 is H or hydroxy, R2 is H or R1 and R2 taken togetherform an oxirane ring, such as, e.g. canarigenin, xysmalogenin,uzarigenin (Fieser L. F. and Fieser M. in "Steroids", 1959, pp. 727-809;Minato H. and Nagasaki T., J. Chem. Soc. (C), 1966, 377),3β-hydroxy-14α-hydroxy-5β-card-20(22)-enolide (Zurcher W. et al., Helv.Chim. Acta, 1969, 52, 2449), 3β-hydroxy-5β,14β-card-20(22)-enolide(Naidoo K., J. Pharm. Science., 1974, 23, 1391),3β-hydroxy-14β,15β-epoxy-carda-4,20(22)-dienolide (Fritsch W. et al.,Ann. Chem., 1969, 727, 110), 3β-acetoxy-14β,15β-epoxy-carda-5,20(22)-dienolide (Yoshii E., Ozaki K.,Chem. Pharm. Bull., 1972, 20, 1585),3β-hydroxy-14β,15β-epoxy-5α-card-20(22)-enolide (DE Pat. 1807585),3β-hydroxy-14α,15α-epoxy-card-20(22)-enolide (Ishii H, Chem. Pharm.Bull., 1963, 11, 576), by reduction with complex hydrides, e.g.diisobutylaluminum-hydride; ##STR4##

or are obtained from known 3-oxo and 17β-lactones (V), wherein R1 ishydroxy, R2 is H or R1 and R2 taken together form an oxirane ring, suchas, e.g. 3-oxo-14β-hydroxy-5α-card-20(22)-enolide (Templeton, J. F. etal., J. Chem. Soc., Perkin Trans. 1, 1983, 251),3-oxo-14β-hydroxy-carda-5,20(22)-dienolide (Volpp G., and Tamm C., Helv.Chim. Acta, (42), 1959, 1408),3-oxo-14β,15β-epoxy-carda-4,20(22)-dienolide (DE Pat. 1812946),3-oxo-14β,15β-epoxy-5α-card-20(22)-enolide (DE Pat. 1807585), byreduction with complex hydrides, e.g. diisobutylaluminum-hydride.##STR5##

Finally, they can be obtained from 3β-hydroxy-androst-5-en-17-one, asdescribed in the experimental section, following known methods.

Compounds of formula (II), wherein X═O, R1 is different from hydrogen orhydroxy and R2 is hydrogen are obtained from the corresponding compoundswherein R1 is hydroxy, by treatment with methyl iodide or with acompound of formula (VI)

    Y-(CH.sub.2).sub.n NR8R9                                   (VI)

wherein Y is an electron-withdrawing group, such as e.g. halogen,mesyloxy, or tosyloxy group, which confers electrophilic properties tothe attached carbon atom and n, R8 and R9 are as above defined: thehydroxy group present in position 3 is protected with methods well knownto those skilled in the art, to give after removal of protective groupthe compounds of general formula (II).

The compounds (II) wherein X═S, R1 and R2 are as above defined, arenovel compounds and are obtained by ammonolysis of the acetylthioderivatives (VII), wherein R1 and R2 are as above defined, ##STR6##which in turn are obtained by reaction of the corresponding 3α-hydroxyderivatives (II) with thiolacetic acid in the presence of a dialkylazodicarboxylate and triphenylphosphine.

The invention furthermore provides a process for the preparation of saidcompounds (I), which comprises the condensation of compounds havingformula (II), wherein X, R1 and R2 are as above defined, with a compoundof formula (VIII)

    R-Y                                                        (VIII)

wherein Y is an electron-withdrawing group, such as halogen, mesyloxy,or tosyloxy group, which confers electrophilic properties to theattached carbon atom, and R is as above defined, the free hydroxy andamino groups, if any, present in R being protected, if necessary, withmethods well known to those skilled in the art to give, after removal ofthe protective groups, if any, compounds of general formula (I) whichmay be converted into other compounds of formula (I) and optionallyconverting compounds (I) into pharmaceutically acceptable salts thereofand optionally separating a mixture of isomers into single isomers.

The condensation reaction between (II) and (VIII) is best carried out inan inert aprotic solvent, such as tetrahydrofuran, dioxane,dimethylformamide, dimethylsulfoxyde or in the neat (VII) and in thepresence of a strong base e.g. sodium or potassium hydride at atemperature ranging from 10° C. to about 110 ° C.

The purification is best performed by flash-chromatography on silicagel.

Examples of conversion of compounds of general formula (I) into othercompounds of formula (I) are the following.

Compounds (I) wherein a C(═NH)NH₂ or a 2-imidazolinyl group are presentcan be obtained by reacting the corresponding compounds of formula(I)wherein a CN group is present with e.g. methylchloroaluminum amide or1,2-diaminoethane in the presence of hydrogen sulfide.

Compounds (I) wherein a guanidino group is present can be obtained byreacting the corresponding compounds of formula (I) wherein a primaryamine is present with e.g. 1-amidino-3,5-dimethylpyrazole nitrate. Allsaid transformations are only examples of well established proceduresdescribed in Organic Chemistry (see for example: J. March "AdvancedOrganic Chemistry", J. Wiley & Sons, 1985; D. Barton and W. D. Ollis"Comprehensive Organic Chemistry", Pergamon Press, 1979) well known tothose skilled in the art.

The compounds of general formula (VI) and (VIII) are known compounds,generally commercially available or preparable from known compounds byknown methods.

The derivatives (I), prepared according to the invention and theirpharmaceutically acceptable salts have much reduced toxicity compared tothe known 17β-(3-furyl)-5β-androstane-3β,14β-diol (II-a: Ref. comp.)(Minato H. and Nagasaki T., J. Chem. Soc.(C), 1966, 377) and are usefulagents for the treatment of cardiovascular disorders such as heartfailure and hypertension. Moreover said compounds (I) show higheraffinity for the receptor site of the Na⁺, K⁺ -ATPase than (II-a) andbehave as partial agonists on the enzymatic activity of the Na⁺,K⁺-ATPase.

To test the affinity for the receptor site of the Na⁺,K⁺ -ATPase and theagonist or antagonist activity on the enzyme, the following tests wereused: a) displacement of the specific ³ H-ouabain binding from theNa⁺,K⁺ -ATPase receptor purified according to Jorghensen (Jorghensen P.,BBA, 1974, 356, 36) and Erdmann ( Erdmann E. et al., Arzneim. Forsh.,1984, 34, 1314); b) inhibition of the activity of the purified Na⁺,K⁺-ATPase measured as % of hydrolysis of ³² P-ATP in presence and inabsence of the tested compound (Mall F. et al., Biochem. Pharmacol.,1984, 33, 47).

The ability of these compounds to lower blood pressure in adulthypertensive MHS rats was tested by the following method: systolic bloodpressure (SBP) and heart rate (HR) were measured by an indirecttail-cuff method in three-month old hypertensive MHS rats beforebeginning treatment (basal values). The rats were then subdivided in twogroups of 7 animals each, one receiving the compound and the other, thecontrol group, receiving only the vehicle. The compound, suspended inMETHOCEL®0.5% (w/v), for ten days, was administered daily by mouth. SBPand HR were measured daily 6 and 24 hours after the treatment. Whenten-day treatment washout had been under way for at least two days,whether the treatment mantains SBP low or re-establish the basal valueswas verified.

The affinity and the inhibitory activity of some ethers and of thereference compound (II-a) in the two tests are shown in the followingtable:

    ______________________________________                                                    Binding .sup.3 H-Ouab.                                                                   Inhibitory                                                         Displacement                                                                             Activity                                                           log IC50                                                                      log IC50                                                          ______________________________________                                        Comp. I - aa  6.8          6.3                                                Comp. I - ab  6.9          5.9                                                Comp. I - ac  6.4          5.7                                                Comp. I - ad  6.8          6.0                                                Comp. I - ae  6.9          6.1                                                Comp. I - af  7.0          5.9                                                Comp. I - ag  6.8          5.8                                                Comp. I - ah  6.8          6.1                                                Comp. I - ai  6.7          6.2                                                Comp. I - aj  6.8          5.9                                                Comp. I - ak  6.8          5.9                                                Comp. I - al  6.9          5.8                                                Comp. I - am  6.7          5.5                                                Comp. I - an  6.7          5.8                                                Comp. I - ao  6.5          5.8                                                Comp. I - ap  6.4          5.8                                                Comp. I - ar  5.5          4.6                                                Comp. I - as  5.3          4.6                                                Comp. I - at  6.2          5.6                                                Comp. I - au  6.5          5.8                                                Comp. I - av  6.2          5.6                                                Comp. I - aw  5.8          5.2                                                Comp. I - ay  6.4          5.5                                                Comp. I - ba  6.2          5.8                                                Comp. I - bc  6.5          5.7                                                Comp. I - bu  6.5          6.2                                                Comp. I - bv  6.3          5.7                                                Comp. I - bw  6.1          5.4                                                Comp. I - bx  6.3          6.0                                                Comp. I - by  6.8          6.0                                                Comp. I - ce  6.0          5.5                                                Comp. I - cj  5.7          5.2                                                Comp. I - cx  6.7          5.8                                                Comp. I - cy  6.4          5.8                                                Comp. I - cz  6.4          5.7                                                Comp. I - da  6.5          5.8                                                Comp. I - db  6.7          5.8                                                Comp. II - a  6.3          5.7                                                ______________________________________                                    

The activity of the Ref. compound II-a and some basic ethers inpreventing the development of hypertension is shown in the followingtable:

    __________________________________________________________________________    SYSTOLIC BLOOD PRESSURE FALL IN                                               SPONTANEOUS HYPERTENSIVE RATS (MHS)                                                        DOSE*    SBP    HR                                               COMPOUNDS                                                                             RATS mg/Kg/os mm Hg  beats/min.                                       __________________________________________________________________________    Controls                                                                              7    METHOCEL ®                                                                         171 ± 4.5                                                                          384 ± 11.0                                   Comp. I-ab                                                                            7    20       157 ± 4.9                                                                          371 ± 10.0                                   Comp. I-ae                                                                            7    20       154 ± 6.3                                                                         395 ± 8.7                                     Comp. I-ag                                                                            7    20       162 ± 5.0                                                                         377 ± 9.0                                     Comp. I-ai                                                                            7    20       160 ± 4.7                                                                         390 ± 8.9                                     Comp. I-al                                                                            7    20       159 ± 5.0                                                                         393 ± 9.0                                     Comp. I-bv                                                                            7    20       161 ± 4.2                                                                         384 ± 6.7                                     Comp. I-bw                                                                            7    20       157 ± 4.3                                                                          392 ± 10.0                                   Comp. I-by                                                                            7    20       154 ± 6.3                                                                         395 ± 8.7                                     Comp. II-a                                                                            7    20       175 ± 4.1                                                                         382 ± 9.0                                     __________________________________________________________________________     *in METHOCEL ® 0.5% w/v                                              

The following examples illustrate the invention without limiting it.

EXAMPLE 1

3β-(2- Aminoethoxy)-17β-(3-furyl)-5β-androstan-14β-ol (I-aa)

To a suspension of 5.5 g of Nail (60% dispersion in mineral oil) in 400ml of dry tetrahydrofuran 7.0 g of17β)-(3-furyl)-5β-androstane-3β,14β-diol (II-a: Ref, comp.) (Minato H.and Nagasaki T., J. Chem. Soc.(C), 1966, 377) were added at roomtemperature in a nitrogen atmosphere. The mixture was kept at reflux for6 hrs, then 26 ml of bromoacetaldehyde diethylacetal were added; thesuspension was kept at reflux temperature for 4 hrs, 50 ml of water wereadded cautiously, and the tetrahydrofuran was distilled under reducedpressure. The residue was extracted with methylene chloride, the organiclayer was dried over anhydrous sodium sulfate and evaporated to drynessunder reduced pressure. The crude product was purified byflash-chromatography (SiO₂) using n-hexane/ethyl acetate 80/20 as eluantto give 6.9 g of3β-(2,2-diethoxy-ethoxy)-17β-(3-furyl)-5β-androstan-14.beta.-ol, as adense oil.

¹ H NMR (300 MHz, CDCl₃, ppm from TMS): 0.72 (3H, s); 0.93 (3H, s); 1.22(6H, t); 2.74 (1H, dd); 3.47-3.50 (2H, m); 3.50-3.80 (5H, m); 4.62 (1H,t); 6.46 (1H, bs); 7.20 (1H, bs); 7.30 (1H, bs).

A solution of 3.8 g of3β-(2,2-diethoxy-ethoxy)-17β-(3-furyl)-5β-androstan-14.beta.-ol, in 300ml of dioxane and 230 ml of a saturated solution of tartaric acid washeated at 70° C. for two hrs in a nitrogen atmosphere, 100 ml of waterwere then added and the residue was extracted with methylene chloride.The organic layer was washed with water., dried over anhydrous sodiumsulfate and evaporated to dryness under reduced pressure. The crudeproduct was purified by flash-chromatography (SiO₂) using as eluantn-hexane/ethyl acetate 70/30 to give 2.0 g of3-β-formylmethoxy-17β-(3-furyl)-5β-androstan-14β-ol as a white solid.

¹ H NMR: (300 MHz, CDCl₃, ppm from TMS): 0.75 (3H, s); 0.95 (3H, s);2.74 (1H, dd); 3.70 (1H, bs); 4.10 (2H, d); 6.48 (1H, bs); 7.20 (1H,bs); 7.32 (1H, bs); 9.78 (1H, t).

To a solution of 2.0 g of3-β-formylmethoxy-17β-(3-furyl)-5β-androstan-14β-ol in 100 ml ofmethanol, 0.30 g of sodium borohydride were added slowly at 0° C. Afterhalf an hr the temperature of the mixture was left to rise to 25° C.After 2 hrs 20 ml of water were added, the methanol was distilled underreduced pressure, and the mixture was extracted with methylene chloride;the organic layer was washed with water, dried over sodium sulfate andevaporated to dryness under reduced pressure. The crude product waspurified by flash-chromatography (SiO₂) using n-hexane/ethyl acetate80/20 as eluant to give 1.8 g of3β-(2-hydroxyethoxy)-17β-(3-furyl)-5β-androstan-14β-ol as a white solid.

¹ H NMR (300 MHz, CDCl₃, ppm from TMS): 0.70 (3H, s); 0.90 (3H, s); 2.72(1H, dd); 3.147 (2H, t); 3.63 (1H, bs); 3.70 (2H, t); 6.44 (1H, bs);7.18 (1H, bs); 7.30 (1H, bs).

A solution of 0.29 ml of diethyl azodicarboxylate was added dropwise,under nitrogen, to a solution of 0.75 g of3β-(2-hydroxyethoxy)-17β-(3-furyl)-5β-androstan-14β-ol, 0.28 g ofphthalimide and 0.50 g of triphenylphosphine in 7 ml of tetrahydrofuranat room temperature. After 2 hrs the solvent was removed in vacuo, thecrude product was dried over anhydrous sodium sulfate and evaporated todryness under reduced pressure. The crude product was purified byflash-chromatography (SiO₂) using n-hexane/ethyl acetate 80/20 to give0.70 g of3β-(2-phthalimidoethoxy)-17β-(3-furyl)-5β-androstan-14.beta.-ol.

¹ H NMR (300 MHz, CDCl₃, ppm from TMS): 0.68 (3H, s); 0.70 (3H, s); 2.72(1H, dd); 3.60-3.68 (3H, m); 3.87-3.95 (2H, m); 6.43 (1H, bs); 7.20 (1H,bs); 7.30 (1H, bs); 7.70-7.76 (2H, m); 7.83-7.92 (2H, m).

To a solution of 0.50 g of3β-(2-phthalimidoethoxy)-17β-(3-furyl)-5β-androstan-14.beta.-ol in 50 mlof ethanol (96%) 0.19 g of hydrazine hydrate were added at roomtemperature. The mixture was kept at reflux for 4 hrs, then 10 ml ofwater were added and the ethanol distilled under reduced pressure. Theresidue was extracted with methylene chloride, the organic solution waswashed with water, dried over anhydrous sodium sulfate and evaporated todryness under reduced pressure. The crude residue was purified byflash-chromatography (SiO₂) using methylene chloride/methanol 90/10 aseluant to give 0.35 g of the title compound (I-aa) as a white solid.

¹ H NMR: (300 MHz, CDCl₃, ppm from TMS): 0.70 (3H, s); 0.92 (3H, s);2.74 (1H, dd); 2.84 (2H, t); 3.41 (2H, m); 3.65 (1H, bs); 6.48 (1H, bs);7.20 (1H, bs); 7.32 (1H, bs).

EXAMPLE 2

3β-(3-Aminopropoxy)-17β-(3-furyl)-5β-androstan-14β-ol (I-ab)

To a solution of 0.60 g of 17β-(3-furyl)-5β-androstane-3β,14β-diol(II-a: Ref. comp.) (Minato H. and Nagasaki T., J. Chem. Soc. (C), 1966,377) in 50 ml of dry tetrahydrofuran, 0.44 g of sodium hydride (60%dispersion in mineral oil) were added under nitrogen atmosphere at roomtemperature and the resulting mixture was stirred at reflux temperaturefor 6 hrs; 1.4 g of allyl bromide were added and the reflux continuedfor further 20 hrs. The mixture was quenched with water and the organicsolvent was distilled under reduced pressure. The residue was extractedwith ethyl acetate, the organic solution was dried over anhydrous sodiumsulfate and evaporated to dryness under reduced pressure. The residuewas purified by flash-chromatography (SiO₂) using n-hexane/ethyl acetate80/20 as eluant to give 0.58 g of3β-(prop-2-enoxy)-17β-(3-furyl)-5β-androstan-14β-ol as a white solid.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.72 (3H, s); 0.92 (3H, s); 2.74(1H, dd); 3.68 (1H, bs); 3.9-4 (2H, m); 5.12-5.18 (1H, m); 5.22-5.33(1H, m); 5.87-6.01 (1H, m), 6.47 (1H, bs); 7.21 (1H, bs); 7.32 (1H, bs).

To a solution of 0.17 g of 9-borabicyclo[3.3.1]nonane in 35 ml of drytetrahydrofuran, 0.50 g of3β-(prop-2-enoxy)-17β-(3-furyl)-5-androstan-14β-ol in 10 ml oftetrahydrofuran were added under nitrogen atmosphere, at roomtemperature. The solution was stirred for 6 hrs then 0.75 ml of ethanol,0.25 ml of sodium hydroxide 6 N and 0.50 ml of hydrogen peroxide 30%were added. The mixture was stirred at 50° C. for an hr, quenched with asolution of 0.76 g of potassium carbonate in 20 ml of water and theorganic solvent distilled under reduced pressure. The residue wasextracted with methylene chloride, the organic solution was dried overanhydrous sodium sulfate and evaporated to dryness under reducedpressure. The residue was purified by flash-chromatography (SiO₂) usingn-hexane/ethyl acetate 70/30 as eluant to give 0.40 g of3β-(3-hydroxypropoxy)-17β-(3-furyl)-5β-androstan-14β-ol as a whiteamorphous solid.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.70 (3H, s); 0.94 (3H, s); 2.74(1H, dd); 3.57-3.67 (3H, m); 3.78-3.83 (2H, m); 6.48 (bs,1H); 7.21 (1H,bs); 7.31 (1H, bs).

0.15 g of 3β-(3-hydroxypropoxy)-17β-(3-furyl)-5β-androstan-14β-ol werefirst changed into the phtalimido derivative 3β-(3-phthalimidopropoxy)-17β-(3-furyl)-5β-androstan-14β-ol and then in0.11 g of the title compound (I-ab) as a white solid, using the sameprocedure described in Ex. 1.

¹ H NMR: (300 MHz, CDCl₃, ppm from TMS): 0.70 (3H, s); 0.91 (3H, s);2.60-2.80 (3H, m); 3.30-3.40 (2H, m); 3.57 (1H, bs); 6.45 (1H, bs); 7.20(1H, bs); 7.31 (1H, bs).

EXAMPLE 3

3β-(4-Aminobutoxy)-17β-(3-furyl)-5β-androstan-14β-ol (I-ac)

To a stirred suspension of 0.50 g of anhydrous lithium chloride in 120ml of anhydrous acetonitrile, 2.7 g of triethyl phosphonoacetate, 1.5 gof 1,8-diazabicyclo[5.4.0]undec-7-ene and 4.0 g of3β-formylmethoxy-17β-(3-furyl)-5β-androstan-14β-ol, prepared asintermediate in Ex.1, were added under nitrogen at room temperature.After an hr, 50 ml of water were added and the organic solvent distilledunder reduced pressure. The residue was extracted with methylenechloride, the organic layer was dried over anhydrous sodium sulfate andevaporated :to dryness under reduced pressure; the crude product waspurified by flash-chromatography (SiO₂), using as eluant n-hexane/ethylacetate 80/20 to give 4.3 g of3β-(3-carbethoxyproβ-2-enoxy)-17β-(3-furyl)-5β-androstan-14β-ol as awhite amorphous solid.

¹ H NMR: (300 MHz, CDCl₃, ppm from TMS): 0.72 (3H, s); 0.93 (3H, s);2.74 (1H, dd); 3.68 (1H, bs); 4.00-4.30 (4H, m); 6.10-6.30 (1H, m); 6.44(1 H, bs); 7.00-7.35 (3 H, m)

To a solution of 0.40 g of3β-(3-carbethoxyprop-2-enoxy)-17β-(3-furyl)-5β-androstan-14β-ol in 30 mlof anhydrous tetrahydrofuran, 2 ml of sodiumbis(2-methoxyethoxy)aluminum hydride (solution 3.4 M in toluene) wereadded at room temperature. The solution was kept at reflux temperaturefor 8 hrs, then 10 ml of water were added and the organic solution wasevaporated to dryness under reduced pressure. The residue was extractedwith ethyl acetate and the organic layer was dried over anhydrous sodiumsulfate and evaporated to dryness under reduced pressure. The crudeproduct was purified by flash-chromatography using n-hexane/ethylacetate 70/30 as eluant to give 0.30 g of3β-(4-hydroxybutoxy)-17β-(3-furyl)-5β-androstan-14β-ol, as a white pastysolid.

¹ H NMR: (300MHz, CDCl₃, ppm from TMS): 0.70 (3H, s); 0.90 (3H, s); 2.74(1H, dd); 3.45-3.65 (3H, m); 3.70-3.90 (2H, m); 6.44 (1H, bs); 7.18 (1H,bs); 7.30 (1H, bs).

0.90 g of 3β(4-hydroxybutoxy)-17β-(3-furyl)-5β-androstan-14β-ol werefirst changed into the phtalimido derivative3β-(4-phthalimidobutoxy)-17β-(3-furyl)-5β-androstan-14.beta.-ol and thenin 0.85 g of the title compound (I-ac) as a white solid, using the sameprocedure described in Ex. 1.

¹ H NMR: (300 MHz, CDCl₃, ppm from TMS): 0.70 (3H, s); 0.90 (3H, s);2.70-2.80 (3H, m); 3.32-3.43 (2H, m); 3.57 (1H, bs); 6.45 (1H, bs); 7.20(1H, bs); 7.31 (1H, bs).

EXAMPLE 4

3β-(2-(1-Pyrrolydinyl)ethoxy)-17β-(3-furyl)-5β-androstan-14.beta.-ol(I-ad)

To a suspension of 0.80 g of NaH (60% dispersion in mineral oil) in 85ml of dry tetrahydrofuran 1.0 g of17β-(3-furyl)-5β-androstane-3β,14β-diol (II-a: Ref. comp.) (Minato H.and Nagasaki T., J. Chem. Soc. (C), 1966, 377) were added at roomtemperature under nitrogen atmosphere. The mixture was kept at refluxfor 6 hrs, then 3.2 g of 1-(2-chloroethyl)pyrrolidine were added; thesuspension was refluxed for 4 hrs, 50 ml of water were added cautiouslyand the tetrahydrofuran was distilled at reduced pressure. The residuewas extracted with methylene chloride, the organic layer was dried overanhydrous sodium sulfate and evaporated to dryness under reducedpressure. The crude product was purified by flash-chromatography (SiO₂)using methylene chloride/methanol 70/30 as eluant to give 0.91 g of thetitle compound (I-ad), as a white solid.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.70 (3H, s); 0.91 (3H, s);2.50-2.62 (4H, m); 2.64-2.80 (3H, m); 3.48-3.58 (2H, m); 3.62 (1H, bs);6.45 (1H, bs); 7.20 (1H, bs); 7.30 (1H, bs).

EXAMPLE 5

3β-(3-(1-Pyrrolydinyl)propoxy)-17β-(3-furyl)-5β-androstan-14β-14β(I-ae)

The title compound (I-ae) (0.65 g) was obtained as a white solid from17β-(3-furyl)-5β-androstane-3β,14β-diol (II-a: Ref. comp.) (Minato H.and Nagasaki T., J. Chem. Soc. (C), 1966, 377) (0.60 g) using the sameprocedure described in Ex. 4.

¹ H-NMR (300 MHz, CDCl₃, ppm :from TMS): 0.72 (3H, s); 0.92 (3H, s);2.46-2.52 (6H, m); 2.74 (1H, dd); 3.42 (2H, t); 3.61 (1H, bs); 6.46 (1H,bs); 7.20 (1H, bs); 7.30 (1H, bs).

EXAMPLE 6

3β-(3-(1-Piperazinyl)propoxy)-17β-(3-furyl)-5β-androstan-14.beta.-ol(I-af)

To a mixture of 0.10 g of 17β-(3-furyl)-5β-androstane-3β,14β-diol (II-a:Ref. comp.) (Minato H. and Nagasaki T., J. Chem. Soc. (C), 1966, 377)and0.078 g of sodium hydride under nitrogen, 0.50 g of4-acetil-1-(3-chloropropyl)-piperazine were added and the resultingsuspension was heated at 90° C. for 3 hrs. To the cooled mixture, 10 mlof water were added, the mixture was extracted with methylene chloride,the organic layer was washed with water, dried over anhydrous sodiumsulfate and evaporated to dryness under reduced pressure. A solution ofthe crude product in 5 ml of methanol and 5 ml of sodium hydroxide 30%was heated at 60° C. for 24 hrs. The organic solvent was distilled underreduced pressure and the aqueous mixture was extracted with methylenechloride. The organic phase was washed with water, dried over anhydroussodium sulfate and evaporated to dryness under reduced pressure. Thecrude product was purified by flash-chromatography (SiO₂) usingmethylene chloride/methanol 90/10 as eluant to give 0.060 g of the titlecompound (I-af), as a white semisolid paste.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.70 (3H, s); 0.90 (3H, s);2.38-2.48 (2H, t); 2.48-2.58 (4H, m); 2.72 (1H, dd); 2.94-3.05 (4H, m);3.37 (2H, t); 3.5.5 (1H, bs); 6.45 (1H, bs); 7.18 (1H, bs); 7.28 (1H,bs).

EXAMPLE 7

3β-(2-(2-(1-Pyrrolidinyl)ethylamino)ethoxy-17β-(3-furyl)-5β-androstan-14β-ol(I-ag)

To a solution of 0.90 g of3β-(2-hydroxyethoxy)-17β-(3-furyl)-5β-andostran-14β-ol, prepared as anintermediate in Ex.1, in 9 ml of dry pyridine, 0.64 g of tosyl chloridewere slowly added at room temperature. After 5 hrs stirring, 10 ml ofwater and 50 ml of ethyl acetate were added, the organic layer waswashed with water and dried over anhydrous sodium sulfate to give 1.2 gof 3β-(2-tosyloxyethoxy)-17β]-(3-furyl)-5β-androstan-14β5-ol as a whitesolid.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.71 (3H, s); 0.90 (3H, s); 2.48(3H, s); 2.74 (1H, dd); 3.52-3.62 (3H, m); 4.15-4.20 (2H, m); 6.46 (1H,bs); 7.20 (1H, bs); 7.30-7.38 (3H, m); 7.78-7.83 (d, 2H).

To a solution of 0.20 g of315-(2-tosyloxyethoxy)-17β-(3-furyl)-5β-androstan-14β-ol in 2 ml ofabsolute ethanol 0.15 g of 1-(2-aminoethyl)pyrrolidine were added. Thesolution was kept at reflux under nitrogen for 3 hrs, then 10 ml ofwater were added. The residue was extracted with methylene chloride, theorganic layer was washed with water to neutral pH, dried over anhydroussodium sulfate and evaporated to dryness under reduced pressure. Thecrude residue was purified by flash-chromatography (SiO₂) usingmethylene chloride/methanol 95/5 as eluant to give 0.15 g of the titlecompound (I-ag).

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.70 (3H, s); 0.90 (3H, s);2.5-2.9 (11H, m); 3.45-3.65 (3H, m); 6.48 (1H, bs); 7.20 (1H, bs); 7.32(1H, bs).

EXAMPLE 8

3β-(2-(2-(1-Pyrrolidinyl)ethoxy)ethoxy),17β-(3-furyl)-5β-androstan-14β-ol (I-ah)

To a suspension of 0.13 g of NaH (60% dispersion in mineral oil) in 15ml of anhydrous dimethylformamide, 0.37 g of1-(2-hydroxyethyl)pyrrolidine were added at room temperature in anitrogen atmosphere. The mixture was kept at reflux for 2 hrs, then 0.90g of 3β-(2-tosyloxy-ethoxy)-17β-(3-furyl)-5β-androstan-14β-ol, preparedas an intermediate in Ex. 7, were added. The mixture was kept at refluxtemperature for 4 hrs; then 50 ml of water were added cautiously. Theresidue was extracted with methylene chloride, the organic layer waswashed with water, dried over anhydrous sodium sulfate and evaporated todryness under reduced pressure. The crude product was purified byflash-chromatography (SiO₂) using acetone/methanol 85/15 as eluant togive 0.70 g of the title compound (I-ah) as a light yellow solid.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.71 (3H, s); 0.91 (3H, s);2.52-2.67 (4H, m); 2.67-2.78 (3H, m); 3.51-3.58 (2H, m); 3.58-3.68 (5H,m); 6.40 (1H, bs); 7.20 (1H, bs); 7.30 (1H, bs)

EXAMPLE 9

3β-(2-(2-(1-Pyrrolidinyl)ethylthio)ethoxy)-17β-(3-furyl)-5β-androstan-14β-ol(I-al)

To a solution of 0.28 g of 1-(2-mercaptoethyl)pyrrolidine in 20 ml ofdimethylformamide, 0.086 g of sodium hydride (60% dispersion in mineraloil) were added under nitrogen atmosphere, and the mixture stirred atroom temperature for half an hr; a DMF solution of 1.0 g of3β-(2-tosyloxyethoxy)-17β-(3-furyl)-5β-androstan-14β-ol, prepared asdescribed in Ex. 7, was added and the mixture was stirred for another 4hrs; the reaction mixture was quenched with water and extracted withmethylene chloride. The organic layer was washed with water, dried overanhydrous sodium sulfate and evaporated to dryness under reducedpressure. The crude product was purified by flash-cromatography (SiO₂)using methylene chloride/methanol 95/5 as eluant and 0.90 g of the titlecompound (I-ai) as a white amorphous solid.

¹ H NMR (300 MHz, CDCl₃, ppm from TMS): 0.70 (3H, s); 0.92 (3H, s);2.20-2.80 (11H, m); 3.58 (2H, m); 3.67 (1H, bs); 6.41 (1H, bs); 7.20(1H, bs); 7.30 (1H, bs).

EXAMPLE 10

3β-(2-(3-Dimethylaminopropoxy)-ethoxy)-17β-(3-furyl)-5β-androstan-14β-ol(I-aj)

The title compound (I-aj) (0.13 g) was obtained as a colourless oil from3β-(2-tosyloxyethoxy)-17β-(3-furyl)-5β-androstan-14β-ol (0.20 g),prepared as described in Ex. 7, using the same procedure described inEx. 8.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.72 (3H, s); 0.93 (3H, s); 2.22(6H, s); 2.31-2.38 (2H, t); 2.74 (1H, dd); 3.48-3.62(6H, m); 3.67 (1H,bs); 6.44 (1H, bs); 7.20 (1H, bs); 7.30 (1H, bs).

EXAMPLE 11

3β-(2-(N-methyl-1-pyrrolydinium)ethoxy)-17β-(3-furyl)-5β-androstan-14β-oliodide (I-ak)

To a 0.037 g of potassium carbonate in 15 ml of methanol, 0.12 g of3β-(2-(1-pyrrolydinyl)ethoxy)-17β-(3-furyl)-5β-androstan-14β-ol (I-ad)and 0.019 ml of methyl iodide were added at room temperature. After 6hrs the methanol was evaporated at reduced pressure. The residue wasdissolved in methylene chloride, the organic layer was washed withwater, dried over anhydrous sodium sulfate and evaporated to drynessunder reduced pressure to give 0.12 g of the title compound (I-ak), as awhite solid which was not submitted to a further purification.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.70 (3H, s); 0.92 (3H, s); 2.74(1H, dd); 3.47 (3H, s); 3.75 (1H, bs); 3.78-4.10 (8H, m); 6.45 (1 H,bs); 7.20 (1 H, bs); 7.32 (1 H, bs).

EXAMPLE 12

3β-(2-Guanidinoethoxy)-17β-(3-furyl)-5β-androstan-14 β-ol nitrate (I-al)

To a solution of 0.17 g of3β-(2-aminoethoxy)-17β-(3-furyl)-5β-androstan-14β-ol (I-aa) in 12 ml ofabsolute ethanol 0.090 g of 3,5-dimethyl-1-pyrazolylformamidiniumnitrate were added and the mixture was kept at reflux for 7 hrs; theethanol was concentrated under reduced pressure and 0.18 g of the titlecompound (1-al) crystallized as a white solid.

¹ H NMR: (300 MHz, DMSO-d6, ppm from TMS): 0.58 (3H, s); 0.85 (3H, s);2.57-2.67 (1H, m); 3.2-3.35 (2H, m); 3.43-3.47 (2H, m); 3.62 (1H, bs);6.42 (1H, bs); 7.32(1H, bs); 7.43 (1H, bs).

EXAMPLE 13

3β-(3-Guanidinopropoxy)-17β-(3-furyl)-5β-androstan-14β-ol nitrate (I-am)

To a solution of 0.10 g of3β-(3-aminopropoxy)-17β-(3-furyl)-5β-androstan-14β-ol (I-ab) in 7 ml ofabsolute ethanol 0.060 g of 3,5-dimethyl-1-pyrazolylformamidiniumnitrate were added and the mixture was kept at reflux temperature for 24hrs; the ethanol was concentrated under reduced pressure and 0.090 g ofthe title compound (I-am) crystallized as a white solid.

¹ H NMR: (300 MHz, DMSO-d6, ppm from TMS): 0.58 (3H, s); 0.85 (3H, s);2.50-2.60(1H, m); 3.14 (2H, m); 3.35 (2H, m); 3.54 (1H, bs); 3.82 (1H,bs); 6.50 (1H, bs); 7.30 (1H, bs); 7.46 (1H, bs).

EXAMPLE 14

3β-(2-Methylaminoethoxy)-17β-(3-furyl)-5β-androstan-14β-ol (I-an)

To 7 ml of a solution of methylamine 3.2 M in methanol, 0.090 g of3β-(2-tosyloxyethoxy)-17β-(3-furyl)-5β-androstan-14β-ol, prepared as anintermediate in Ex.7, were added. The solution was kept at reflux undernitrogen for 11 hrs, then was evaporated. The resulting solid was washedwith n-hexane to give 0.045 g of the title compound (I-an) as a lightyellow pasty solid.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.72 (3H, s); 0.92 (3H, s); 2.54(3H, s); 2.74 (1H, dd); 2.82 (2H, t); 3.00-3.08 (2H, m); 3.68 (1H, bs);6.47 (1H, s); 7.22 (1H, s); 7.33 (1H, s).

EXAMPLE 15

3β-(2,3-Diaminopropoxy)-17β-(3-furyl)-5β-androstan-14β-ol (I-ao)

To a mixture of 0.70 g of N-Methylmorpholine-N-oxide, 6.5 ml of water,13.7 ml of acetone and 1.64 ml of a 0.06 M ethereal osmium tetroxidesolution, 2.0 g of 3β-prop-2-enoxy-17β(3-furyl)-5β-androstan-14β-ol,prepared as an intermediate in Ex.2, dissolved in 29 ml of tert-butanolwere added at room temperature. The mixture was left on standing for 20hrs, 50 ml of a saturated sodium hydrosulfite solution and 2.0 g ofcelite were added, the mixture was stirred for 2 hrs and then filtered.The organic solvent was distilled under reduced pressure, the aqueousphase was extracted with methylene chloride, the organic layer was driedover anhydrous sodium sulfate and evaporated to dryness under reducedpressure. The crude product was purified by flash-chromatography (SiO₂)using n-hexane/ethyl acetate 20/80 as eluant to give 1.8 g of3β-(2,3-dihydroxypropoxy)-17β-(3-furyl)-5β-androstan-14.beta.-ol as awhite solid.

¹ H NMR (300 MH_(z), CDCl₃, ppm from TMS): 0.70 (3H, s); 0.95 (3H, s);2.32-2.48 (1H, m); 2.67-2.82 (2H, m); 3.46-3.60 (2H, m); 3.68 (1H, bs);3.70-3.79 (2H, m); 3.82-3.92 (1H, m); 6.48 (1H, bs); 7.20 (1H, bs); 7.32(1H, bs).

To a solution of 0.92 g of3β-(2,3-dihydroxypropoxy)-17β(3-furyl)-5β-androstan-14.beta.ol, in 6.6ml of dry pyridine, 0.84 g of tosyl chloride were added at a temperatureof 0° C. After 5 hrs 15 ml of water and 60 ml of ethyl, acetate wereadded, the organic layer was washed with water, dried over anhydroussodium sulfate and evaporated to dryness under reduced pressure. Thecrude product was purified by flash-chromatography (SiO₂) usingn-hexane/ethyl acetate 80/20 as eluant to give 1.3 g of3β-(2,3-ditosyloxypropoxy)-17β-(3-furyl)-5β-androstan-14.beta.-ol as awhite solid.

¹ H NMR (300 MH_(z), CDCl₃, ppm from TMS): 0.71 (3H, s); 0.88 (3H, s);2.45 (6H, bs); 2.74 (1H, dd); 3.45-3.55 (3H, m); 4.05-4.18 (2H, m); 4.62(1H, bs); 6.47 (1H, bs); 7.22 (1H, bs); 7.30-7.40 (5H, m); 7.70-7.82(4H, m).

To a solution of 1.3 g of3β-(2,3-ditosyloxypropoxy)-17β-(3-furyl)-5β-androstan-14.beta.-ol in 10ml of dimethylsulfoxide 1.1 g of sodium azide were added at roomtemperature. The solution was kept at reflux for 3 hrs, then 5 ml ofwater were added and the residue was extracted with methylene chloride.The organic layer was washed with water, dried over anhydrous sodiumsulfate and evaporated to dryness under reduced :pressure. The crudeproduct was purified by flash-chromatography (SiO₂)using n-hexane/ethylacetate 80/20 as eluant to give 0.75 g3β-(2,3-diazidopropoxy)-17β-(3-furyl)-5β-androstan-14β-ol.

¹ H NMR: (300 MHz, CDCl₃, ppm from TMS): 0.72 (3H, s); 0.94 (3H, s);2.74 (1H, m); 3.4-3.7 (5H, m); 3.68 (1H, bs); 6.48 (1H, bs); 7.20 (1 H,bs); 7.31 (1 H, bs).

A solution of 0.44 g of 3β-(2,3-diazidopropoxy)-17β-(3-furyl)-5β-androstan-14β-ol in 9 ml of diethyl ether is added to a suspension of0.20 g of lithium aluminium hydride in 6 ml of diethyl ether.

The mixture was kept at reflux for 12 hrs then in succession were added0.44 ml of water, 0.44 ml of sodium hydroxyde (water solution 10%) and1.76 ml of water. The mixture was filtered over a celite cake, theorganic solution was washed with water, dried over sodium sulfate andevaporated to dryness under reduced pressure. The crude residue waspurified by flash-chromatography (SiO₂) using methylenechloride/methanol/30% ammonia solution 90/10/1 as eluant to give 0.29 gof the title compound (I-ao) a white solid.

¹ H NMR (300 MH_(z), CDCl₃, ppm from TMS): 0.70 (3H, s); 0.90 (3H, s);2.70-3.50 (6H, m); 3.68 (1H, bs); 6.48 (1H, bs); 7.20 (1H, bs); 7.32(1H, bs).

EXAMPLE 16

3β(2,3-Bis(1-pyrrolidinyl)propoxy)-17β-(3-furyl)-5β-androstan-14β-ol(I-ap)

To a solution of 0.16 g of3β-(2,3-ditosyloxypropoxy)-17β-(3-furyl)-5β-androstan-14.beta.-ol,prepared as an intermediate in Ex.15, in 1.5 ml of absolute ethanol, 1 gof pyrrolidine were added at room temperature. The solution was kept atreflux for 3 hrs, then 10 ml of water were added and the residue wasextracted with methylene chloride. The organic layer was washed withwater to neutral pH, dried over anhydrous sodium sulfate and evaporatedto dryness under reduced pressure. The crude product was purified byflash-chromatography (SiO₂) using methylene chloride/methanol 95/5 aseluant to give 0.92 g of the title compound (1-ap) as a light yellowamorphous solid.

¹ H NMR (300 MHz, CDCl₃, ppm from TMS): 0.72 (3H, s); 0.92 (3H, s);2.51-2.79 (12H, m); 3.49-3.65 (3H, m); 6.47 (1H, bs); 7.22 (1H, bs);7.32 (1H, bs).

EXAMPLE 17

3β,14β-Bis(2-(1-pyrrolidinyl)ethoxy)-17β-(3-furyl)-5β-androstane (I-aq)

The title compound (I-aq) (0.12 g) was obtained as a white solid from17β-(3-furyl)-5β-androstane-3β,14β-diol (II-a: Ref. comp.) (Minato H.and Nagasaki T., J. Chem. Soc. (C), 1966, 377) (0.10 g) using the sameprocedure described in Ex. 4, but the reaction was kept at refluxtemperature for 24 hrs, instead of 4 hrs.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.78 (3H, s); 0.94 (3H, s);2.50-2.80 (12H, m); 3.48-3.56 (2H, m); 3.58-3.70 (3H, m); 6.42 (1H, bs);7.2 (1H, bs); 7.3 (1H, bs).

EXAMPLE 18

3β-(3-Aminoproproxy)-14β-methoxy-17β-(3-furyl)-5β-androstane (I-ar)

The title compound (I-ar) (0.22 g) was obtained as a white solid from14β5-methoxy-17β-(3-furyl)-5β-androstan-3β-ol (II-c, Prep. 2) (1.0 g)using the same procedure described in Ex. 2.

¹ H-NMR (300 MHz, CDOD₃, ppm from TMS): 0.78 (3H, s); 1.00 (3H, s);2.70-2.85 (3H, m); 3.35 (3H, m); 3.46 (3H, m); 3.62 (1H, bs); 6.40 (1H,bs); 7.18 (1H, bs); 7.35 (1H, bs).

EXAMPLE 19

3β-(2-(1-Pyrrolydinyl)ethoxy)-14β-methoxy-17β-(3-furyl)-5.beta.-androstaneoxalate (I-as)

To a suspension of 0.50 g of NaH (60% dispersion in mineral oil) in 85ml of dry tetrahydrofuran 0.45 g of14β-methoxy-17β-(3-furyl)-5β-androstan-3β-ol (II-c, Prep. 2) were addedat room temperature in a nitrogen atmosphere. The mixture was kept atreflux for 6 hrs, then 2.0 g of 1-(2-chloroethyl)pyrrolidine were added;the suspension was kept at reflux temperature for 4 hrs, 50 ml of waterwere added cautiously and the tetrahydrofuran was distilled underreduced pressure. The residue was extracted with methylene chloride, theorganic layer was dried over anhydrous sodium sulfate and evaporated todryness under reduced pressure. The crude product was purified byflash-chromatography (SiO₂) using methylene chloride/methanol 70/30 aseluant to give the pure compound that was successively treated withoxalic acid to give 0.30 g of the title compound (I-as) as a whitesolid.

¹ H-NMR (300 MHz, CDOD₃, ppm from TMS): 0.78 (3H, s); 1.0 (3H, s); 2.72(1H, m); 3.35 (3H, s); 3.40 (6H, m); 3.75 (3H, m); 6.40 (1H, bs); 7.18(1H, bs); 7.35 (1H, bs).

EXAMPLE 20

3β-(3-Aminopropoxy)-17β-(3-furyl)-androst-4-en-14β-ol (I-at)

The title compound (I-at) (0.15 g) was obtained as a white solid from17β-(3-furyl)-androst-4-ene-3β,14β-diol (prepared from canarigenin asdescribed in Minato H., and Nagasaki T., J. Chem. Soc. (C), 1966,377)(1.0 g) using the same procedure described in Ex. 2.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.71 (3H, s); 1.09 (3H, s);2.70-2.85 (3H, m); 3.46 (2H, m); 4.01 (1H, m); 5.40 (1H, bs); 6.53 (1H,bs); 7.20 (1H, bs); 7.35 (1H, bs).

EXAMPLE 21

3β-(2-(1-Pyrrolidinyl)ethoxy)-17β-(3-furyl)-androst-4-en-14β-ol oxalate(I-au)

The title compound (I-au) (0.25 g) was obtained as a white solid from17β-(3-furyl)-androst-4-ene-3β,14β-diol (prepared from canarigenin asdescribed in Minato H., and Nagasaki T., J. Chem. Soc. (C), 1966, 377)(0.28 g) using the same procedure described in Ex. 19.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.71 (3H, s); 1.09 (3H, s); 2.72(1H, dd); 3.22-3.65 (6H, m); 3.78 (2H, m); 4.01 (1H, m); 5.40 (1H, bs);6.53 (1H, bs); 7.20 (1H, bs); 7.35 (1H, bs).

EXAMPLE 22

3β-(Aminopropoxy)-17β-(3-furyl)-androst-5-en-14β-ol (I-av)

The title compound (I-av) (0.090 g) was obtained as a white solid from17β-(3-furyl)-androst-5-ene-3β,14β-diol (prepared from xysmalogenin asdescribed in Minato H., and Nagasaki T., J. Chem. Soc. (C), 1966,377)(0.70 g) using the same procedure described in Ex. 2.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.51 (3H, s); 0.98 (3H, s);2.70-2.85 (3H, m); 3.10-3.25 (1H, m); 3.46 (2H, m); 5.38 (1H, bs); 6.30(1H, bs); 7.28 (1H, bs); 7.38 (1H, bs).

EXAMPLE 23

3β-(2-(1-Pyrrolidinyl)ethoxy)-17β-(3-furyl)-androst-25-en-14.beta.-ol(I-aw)

The title compound (I-aw) (0.26 g) was obtained as a white solid from17β-(3-furyl)-androst-5-ene-3β,14β-diol (prepared from xysmalogenin asdescribed in Minato H., and Nagasaki T., J. Chem. Soc. (C), 1966, 377)(0.30 g) using the same procedure described in Ex. 4.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.51 (3H, s); 0.98 (3H, s);2.50-2.60 (4H, m); 2.69 (2H, t); 3.10-3.25 (1H, m); 3.63 (1H, t); 5.38(1H, bs); 6.30 (1H, bs); 7.28 (1H, bs); 7.38 (1H, bs).

EXAMPLE 24

3β-(3-Aminopropoxy)-17β-(3-furyl)-5α-androstan-14β-ol (I-ax)

The title compound (1-ax) (0.030 g) was obtained as a light jellow solidfrom 17β-(3-furyl)-5α-androstane-3β,14β-diol (prepared from uzarigeninas described in Minato H., and Nagasaki T., J. Chem. Soc. (C), 1966,377)(0.30 g) using the same procedure described in Ex. 2.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.51 (3H, s); 0.98 (3H, s);2.70-2.85 (3H, m); 3.28 (1H, m); 3.46 (2H, m); 6.48 (1H, bs); 7.21 (1H,bs); 7.32 (1H, bs).

EXAMPLE 25

3β-(2-(1-Pyrrolidinyl)ethoxy)-17β-(3-furyl)-5α-androstan-14β-ol (I-av)

The title compound (I-ay) (0.070 g) was obtained as a white solid from17β-(3-furyl)-5a-androstane-3β,14β-diol (prepared from uzarigenin asdescribed in Minato H., and Nagasaki T., J. Chem. Soc. (C), 1966, 377)(0.10 g) using the same procedure described in Ex. 4.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.51 (3H, s); 0.98 (3H, s); 2.58(4H, bs); 2.65-2.75 (3H, m) 3.28 (1H, m); 3.52 (2H, m); 6.48 (1H, bs);7.21 (1H, bs); 7.32 (1H, bs).

EXAMPLE 26

3β-(3,Aminopropoxy)-14β,15β-epoxy-17β-(3-furyl)-5β-androstane (I-az)

The title compound (I-az) (0.090 g) was obtained as a white solid from14β,15β-epoxy-17β-(3-furyl)-5β-androstan-3β-ol (E. Yoshii et al., Chem.Pharm. Bull, 1976,24,3216)(0.60 g) using the same procedure described inEx. 2.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.76 (3H, s); 1.00 (3H, s); 2.36(1H, m); 2.70-2.85 (3H, m); 3.46 (2H, m); 3.56 (1H, bs); 3.65 (1H, bs);6.42 (1H, bs); 7.18 (1H, bs); 7.29 (1H, bs).

EXAMPLE 27

3β-(2-(1-Pyrrolidinyl)ethoxy)-14β,15β-epoxy-17β-(3-furyl)-5β-androstaneoxalate (I-ba)

The title compound (1-ba) (0.60 g) was obtained as a white solid from14β,15β-epoxy-17β-(3-furyl)-5β-androstan-3β-ol (E. Yoshii et al., Chem.Pharm. Bull., 1976, 24, 3216) (0.75 g) using the same proceduredescribed in Ex. 19.

¹ H-NMR (300 MHz, CDCl3, ppm from TMS): 0.76 (3H, s); 1.00 (3H, s); 2.11(4H, bs); 2.36 (1H, m); 2.71 (1H, d); 3.42 (2H, m); 3.56 (1H, s); 3.71(3H, bs); 6.42 (1H, bs); 7.18 (1H, bs); 7.29 (1H, bs).

EXAMPLE 28

3β-(3-Aminopronoxy)-14β,15β-epoxy-17β-(3-furyl)-androst-4-ene (I-bb)

The title compound (I-bb) (0.10 g) was obtained as a white solid from14β,15β-epoxy-17β-(3-furyl)-androst-4-en-3β-ol (prepared from3β-hydroxy-14β,15β-epoxy-carda-4,20(22)-dienolide, W. Fritsch et al.,Ann. Chem., 1969, 727, 110, E. Yoshii et al., Chem. Pharm. Bull, 1976,24, 3216)(0.60 g) using the same procedure described in Ex. 2.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.71 (3H, s); 1.00 (3H, s); 2.36(1H, m); 2.65-2.75 (3H, m); 3.46 (2H, m); 3.56 (1H, bs). 4.01 (1H, m);5.40 (1H, bs); 6.53 (1H, bs); 7.20 (1H, bs); 7.35 (1H, bs).

EXAMPLE 29

3β-(2-(1-Pyrrolidinyl)ethoxy)-14β,15β-epoxy-17β-(3-furyl)-androst-4-ene(I-bc)

The title compound (I-bc) (0.28 g) was obtained as a white solid from14β,15β-epoxy-17β-(3-furyl)-androst-4-en-3β-ol (prepared from3β-hydroxy-14β,15β-epoxy-carda-4,20(22)-dienolide, W. Fritsch et al.,Ann. Chem., 1969, 727, 110, E. Yoshii et al., Chem. Pharm. Bull, 1976,24, 3216) (0.30 g) using the same procedure described in Ex. 4.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.71 (3H, s); 1.00 (3H, s); 2.36(1H, m); 2.58 (4H, bs); 2.65-2.75 (3H, m); 3.50-3.60 (3H, m). 4.01 (1H,m); 5.40 (1H, bs); 6.43 (1H, bs); 7.18 (1H, bs); 7.29 (1H, bs).

EXAMPLE 30

3β-(3-Aminopropoxy)-14β,15β-epoxy-17β-(3-furyl)-androst-5-ene (I-bd)

The title compound (I-bd) (0.090 g) was obtained as a colourless oilfrom 14β,15β-epoxy-17β-(3-furyl)-androst-5-en-3β-ol (prepared fromxysmalogenin as described in Fritsch W. et al., Ann. Chem., 1969, 727,110, E. Yoshii et al., Chem. Pharm. Bull, 1976, 24, 3216) (0.60 g) usingthe same procedure described in Ex. 2.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.51 (3H, s); 1.07 (3H, s);2.70-2.85 (3H, m); 3.15-3.25 (1H, m); 3.46 (2H, m); 3.56 (1H, bs); 5.40(1H, bs); 6.48 (1H, bs); 7.20 (1H, bs); 7.35 (1H, bs).

EXAMPLE 31

3β-(2-(1-Pyrrolidinyl)ethoxy)-14β,15β-epoxy-17β-(3-furyl)-androst-5-ene(I-be)

The title compound (I-be) (0.30 g) was obtained as a white solid from14β,15β-epoxy-17β-(3-furyl)-androst-5-en-3β-ol (prepared fromxysmalogenin as described in W. Fritsch et al., Ann. Chem., 1969, 727,110, E. Yoshii et al., Chem. Pharm. Bull, 1976, 24, 3216) (0.30 g) usingthe same procedure described in Ex. 4.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.51 (3H, s); 1.07 (3H, s);2.51-2.63 (4H, bs); 2.65-2.80 (3H, m); 3.15-3.25 (1H, m); 3.51-3.61 (3H,m). 5.40 (1H, bs); 6.48(1H, bs); 7.20 (1H, bs); 7.35 (1H, bs).

EXAMPLE 32

3β-(3-Aminopropoxy)-14β,15β-epoxy-17β-(3-furyl)-5 α-androstane (I-bf)

The title compound (I-bf) (0.020 g) was obtained as a white solid from14β,15β-epoxy-17β-(3-furyl)-5α-androstan-3β-ol (prepared from3β-hydroxy-14β,15β-epoxy-5α-card-20(22)-enolide, DE Pat. 1807585, E.Yoshii et al., Chem. Pharm. Bull, 1976, 24, 3216)(0.40 g) using the sameprocedure described in Ex. 2.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.51 (3H, s); 1.00 (3H, s); 2.36(1H, m); 2.70-2.85 (3H, m); 3.28 (1H, m); 3.46 (2H, m); 3.56 (1H, bs);6.42(1H, bs); 7.18 (1H, bs); 7.29 (1H, bs).

EXAMPLE 33

3β-(2-(1-Pyrrolidinyl)ethoxy)-14β,15β-epoxy-17β-(3-furyl)-5α-androstane(I-bg)

The title compound (I-bg) (0.080 g) was obtained as a light yellow solidfrom 14β,15β-epoxy-17β-(3-furyl)-5α-androstan-3β-ol (prepared from3β-hydroxy-14β,15β-epoxy-5α-carda-20(22)-dienolide, DE Pat. 1807585,-E.Yoshii et al., Chem. Pharm. Bull, 1976, 24, 3216) (0.10 g) using thesame procedure described in Ex. 4.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.51 (3H, s); 1.00 (3H, s); 2.36(1H, m); 2.58 (4H, bs); 2.65-2.75 (3H, m); 3.28 (1H, m); 3.50-3.60 (3H,m); 6.42 (1H, bs); 7.18 (1H, bs); 7.29 (1H, bs).

EXAMPLE 34

3β-(3-Aminopropoxy)-14α,15β-epoxy-17α-(3-furyl)-5.beta.-androstane(I-bh)

The title compound (I-bh) (0.050 g) was obtained as a white solid from14α,15α-epoxy-17β-(3-furyl)-5β-androstan-3β-ol (prepared from3β-hydroxy-14α,15α-epoxy-card-20(22)-enolide, Ishii H, Chem. Pharm.Bull, 1963, 11, 576, Minato H., and Nagasaki T., J. Chem. Soc. (C),1966,377)(0.35 g) using the same procedure described in Ex. 2.

H¹ -NMR (300 MHz, CDCl₃, ppm from TMS): 0.66 (3H, s); 0.98 (3H, s); 2.65(1H, dd); 2.72 (2H, m); 3.42-3.55 (3H, m); 3.63 (1H, bs); 6.19 (1H, bs);7.18 (1H, bs); 7.29 (1H, bs).

EXAMPLE 35

3β-(2-(1-pyrrolidinyl)ethoxy)-14β,15β-epoxy-17β-(3-furyl)-5β-androstane(I-bi)

The title compound (I-bi) (0.085 g) was obtained as a white solid from14β,15β-epoxy-17β(3-furyl)-5β-androstan-3β-ol (prepared from3β-hydroxy-14α,15α-epoxy-card-20(22)-enolide, Ishii H, Chem. Pharm.Bull., 1963, 11, 576, Minato H., and Nagasaki T., J. Chem. Soc. (C),1966, 377) (0.10 g) using the same procedure described in Ex. 4.

H¹ -NMR (300 MHz, CDCl₃, ppm from TMS): 0.66 (3H, s); 0.98 (3H, s);2.55-2.77 (7H, m); 3.50-3.60 (3H, m); 3.63 (1H, bs); 6.19 (1H, bs); 7.18(1H, bs); 7.29 (1H, bs).

EXAMPLE 36

3β-(2-(1-Pyrrolidinyl)ethoxy)-17β-(3-furyl)-5β,14β-androstane (I-bi)

The title compound (I-bj) (0.050 g) was obtained as a white solid from17β-(3-furyl)-5β,14β-androstan-3β-ol (prepared from3β-hydroxy-5β,14β-card-20(22)-enolide, Naidoo K., J. Pharm. Science.,1974, 23, 1391, Minato H., and Nagasaki T., J. Chem. Soc. (C), 1966,377) (0.070 g) using the same procedure described in Ex. 4.

H¹ -NMR (300 MHz, CDCl₃, ppm from TMS): 0.71 (3H, s); 0.92 (3H, s);2.52-2.78 (7H, m); 3.52 (2H, m); 3.63 (1H, bs); 6.21 (1H, bs); 7.14 (1H,bs); 7.32 (1H, bs).

EXAMPLE 37

3β-(3-Aminopropoxy)-17β-(3-furyl)-androst-4-ene (I-bk)

The title compound (I-bk) (0.15 g) was obtained as a white solid from17β-(3-furyl)-androst-4-en-3β-ol (prepared from17β-(3-furyl)-androst-4-en-3-one, described in U.S. Pat. No. 3436390,with known procedures) (0.60 g) using the same procedure described inEx. 2.

H¹ -NMR (300 MHz, CDCl₃, ppm from TMS): 0.71 (3H, s); 0.82 (3H, s); 2.45(1H, m); 2.83 (2H, m); 3.46 (2H, m); 4.01 (1H, m); 6.28 (1H, bs); 7.18(1H, bs); 7.36 (1H, bs).

EXAMPLE 38

3β-(2-(1-Pyrrolidinyl)ethoxy)-17β-(3-furyl)-androst-4-ene (I-bl)

The title compound (I-bl) (0.27 g) was obtained as a white solid from17β-(3-furyl)-androst-4-en-3β-ol (prepared from17β-(3-furyl)-androst-4-en-3-one, described in U.S. Pat. No. 3436390,with known procedures) (0.30 g) using the same procedure described inEx. 4.

H¹ -NMR (300 MHz, CDCl3, ppm from TMS): 0.71 (3H, s); 0.82 (3H, s); 2.45(1H, m); 2.58 (4H, bs); 2.65-2.75 (2H, m); 3.52 (2H, m); 4.01 (1H, m);6.28 (1H, bs); 7.18 (1H, bs); 7.36 (1H, bs).

EXAMPLE 39

3β-(3-Aminopropoxy)-17β-(3-furyl)-androst-5-ene (I-bm)

The title compound (I-bm) (0.13 g) was obtained as a white solid from17β-(3-furyl)-androst-5-en-3β-ol (prepared from3β-hydroxy-androst-5-en-17-one in the same manner described in U.S. Pat.No. 3436390) (0.60 g) using the same procedure described in Ex. 2.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.51 (3H, s); 0.98 (3H, s); 2.83(2H, m); 3.10-3.25 (1H, m); 3.53 (2H, m); 5.38 (1H, bs); 6.30 (1H, bs);7.28 (1H, bs); 7.38 (1H, bs).

EXAMPLE 40

3β-(2-(1-Pyrrolidinyl)ethoxy)-17β-(3-furyl)-androst-5-ene (I-bn)

The title compound (I-bn) (0.31 g) was obtained as a white solid from17β-(3-furyl)-androst-5-en-3β-ol (prepared from3β-hydroxy-androst-5-en-17-one in the same manner described in U.S. Pat.No. 3436390) (0.30 g) using the same procedure described in Ex. 4.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.51 (3H, s); 0.98 (3H, s);2.50-2.60 (4H, m); 2.69 (2H, t); 3.10-3.25 (1H, m); 3.63 (1H, t); 5.38(1H, bs); 6.30 (1H, bs); 7.28 (1H, bs); 7.38 (1H, bs).

EXAMPLE 41

3β-(3-Aminopropoxy)-17β-furyl)-5α-androstane (I-bo)

The title compound (I-bo) (0.17 g) was obtained as a white solid from17β-(3-furyl)-5α-androstan-3β-ol (U.S. Pat. No. 3436390) (0.60 g) usingthe same procedure described in Ex. 2.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.51 (3H, s); 0.82 (3H, s); 2.45(1H, m); 2.83 (2H, m); 3.28 (1H, m); 3.46 (2H, m); 6.28 (1H, bs); 7.18(1H, bs); 7.36 (1H, bs).

EXAMPLE 42

3β-(2-(1-Pyrrolidinyl)ethoxy)-17β-(3-furyl)-5α-androstane (I-bp)

The title compound (I-bp) (0.15 g) was obtained as a white solid from17β-(3-furyl)-5α-androstan-3β-ol (U.S. Pat. No. 3436390) (0.15 g) usingthe same procedure described in Ex. 4.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.51 (3H, s); 0.82 (3H, s); 2.45(1H, m); 2.58 (4H, bs); 2.70 (2H, m); 3.28 (1H, m); 3.52 (2H, m); 6.28(1H, bs); 7.18 (1H, bs); 7.36 (1H, bs).

EXAMPLE 43

3α-(3-Aminopropoxy)-17β-(3-furyl)-5β-androstan-14β-ol (I-bq)

The title compound (I-bq) (0.15 g) was obtained as a white solid from17β-(3-furyl)-5β-androstane-3α,14β-diol (Humber D. et al., Steroids,1983, 42, 189) (0.60 g) using the same procedure described in Ex. 2.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.71 (3H, s); 0.97 (3H, s); 2.74(1H, dd); 2.82 (2H, m); 3.28 (1H, m);. 3.46 (2H, m); 6.48 (1H, bs); 7.21(1H, bs); 7.32 (1H, bs).

EXAMPLE 44

3α-(2-(1-Pyrrolydinyl)ethoxy)-17β-(3-furyl)-5β-androstan-14β5-ol (I-br)

The title compound (I-br) (0.34 g) was obtained as a white solid from17β-(3-furyl)-5β-androstane-3α,14β-diol (Humber D. et al., Steroids,1983, 42, 189) (0.35 g) using the same procedure described in Ex. 4.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.70 (3H, s); 0.92 (3H, s);2.50-2.62 (4H, m); 2.65-2.82 (3H, m); 3.20-3.35 (1H, m); 3.58-3.68 (2H,m); 6.45 (1H, bs); 7.20 (1H, bs); 7.30 (1H, bs).

EXAMPLE 45

3α-(3-Aminopropoxy)-14β,15β-epoxy-17β-(3-furyl)-5.beta.-androstane(I-bs)

The title compound (I-bs) (0.14 g) was obtained as a white solid from14β,15β-epoxy-17β-(3-furyl)-5β-androstan-3a-ol (II-b, Prep. 1)(0.60 g)using the same procedure described in Ex. 2.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.76 (3H, s); 1.00 (3H, s); 2.36(1H, m); 2.70-2.85 (3H, m); 3.28 (1H, m); 3.46 (2H, m); 3.56 (1H, bs);6.42 (1H, bs); 7.18 (1H, bs); 7.29 (1H, bs).

EXAMPLE 46

3α(2-(1-Pyrrolidinyl)ethoxy)-14β,15β-epoxy-17β-(3-furyl)-5.15-androstane(I-bt)

The title compound (I-bt) (0.34 g) was obtained as a white solid from14β,15β-epoxy-17β-(3-furyl)-5β-androstan-3α-ol (II-b, Prep. 1) (0.35 g)using the same procedure described in Ex. 4.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.76 (3H, s); 1.00 (3H, s); 2.36(1H, m); 2.50-2.62 (4H, m); 2.68-2.77 (3H, m); 3.28 (1H, m); 3.50-3.60(3H, m); 6.4.2 (1H, bs); 7.18 (1H, bs); 7.29 (1H, bs).

EXAMPLE 47

3β-(2-(4-Morpholinoethylthio)-17β-(3-furyl)-5β-androstan-14.beta.-oloxalate (I-bu)

To a solution of 0.19 g of 3β-mercapto-17β-(3-furyl)-5β-androstan-14β-ol(II-d, Prep. 3) and 0.33 ml of 4-(2-chloroethyl)morpholine in 5.0 ml oftetrahydrofuran under nitrogen atmosphere at room temperature, 0.030 gof sodium hydride (60% dispersion in mineral oil) were added. Thereaction mixture was stirred for 40 hrs, diluted with water andextracted with ethyl acetate; the organic layer was dried over sodiumsulfate and evaporated to dryness under reduced pressure. The crudeproduct was purified by flash-chromatography (SiO₂) using methylenechloride/methanol/30% ammonia solution 95/5/1 as eluant and successivelytreated with oxalic acid to give 0.20 g of the title compound (I-bu) asa white solid.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.72 (3H, s); 0.95 (3H, s);2.45-2.55 (2H, m); 2.75 (1H, dd); 3.25 (1H, bs); 3.72 (4H, t); 6.48 (1H,bs); 7.21 (1H, bs); 7.32 (1H, bs).

EXAMPLE 48

3β-(2-Aminoethylthio)-17β-(3-furyl)-5β-androstan-14β-ol oxalate (I-bv)

The title compound (I-bv) (0.20 g) was obtained as a white solid from3β-mercapto-17β-(3-furyl)5β-androstan-14β-ol (II-d, Prep. 3)(0.30 g)using the same procedure described in Ex. 47.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.72 (3H, s); 0.95 (3H, s); 2.58(2H, t); 2.75 (1H, dd); 2.79 (2H, t); 3.22 (1H, bs); 6.48 (1H, bs); 7.21(1H, bs); 7.32 (1H, bs).

EXAMPLE 49

3β-(2-(1-Pyrrolidinyl)ethylthio)-17β-(3-furyl)-5β-androstan-14β-ol(I-bw)

The title compound (I-bw) (0.18 g) was obtained as a pale yellow solidfrom 3β-mercapto-17β(3-furyl)-5β-androstan-14β-ol (II-d, Prep. 3)(0.30g) using the same procedure described in Ex. 47.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.72 (3H, s); 0.95 (3H, s);2.50-2.60 (4H, m); 2.60-2.70 (4H, m); 2.75 (1H, dd); 3.26 (1H, bs); 6.48(1H, bs); 7.21 (1H, bs); 7.32 (1H, bs).

EXAMPLE 50

3β-(3-(1-Piperazinyl)propylthio)-17β-(3-furyl)-5,β)-androstan-14β-oldioxalate(I-bx)

The title compound (I-by) (0.33 g) was obtained as a pale yellow solidfrom 3β-mercapto-17β-(3-furyl)-5β-androstan-14β-ol (II-d, Prep. 3)(0.30g) using the same procedure described in Ex. 47.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.72 (3H, s); 0.95 (3H, s); 2.42(6H, bt); 2.52 (2H, t); 2.75 (1H, dd); 2.90 (4H, t); 3.24 (1H, bs); 6.48(1H, bs); 7.21 (1H, bs); 7.32 (1H, bs).

EXAMPLE 51

3β-(2-(2-(1-Pyrrolidinyl)ethoxy)ethylthio)-17β-(3-furyl)-5β-androstan-14β-ol(I-by)

To a solution of 1.5 g of 3β-mercapto-17β-(3-furyl)-5β-androstan-14β-ol(II-d, Prep. 3) in 20 ml of dimethylformamide, where nitrogen wascontinuously bubbled in, 1.0 ml of 2-bromoethanol and 0.18 g of sodiumhydride (60% dispersion in mineral oil) were added at room temperature.The reaction mixture was stirred for 7 hrs, then diluted with water andextracted with ethyl acetate. The organic solution was washed withwater, dried over sodium sulfate and evaporated to dryness under reducedpressure. The crude product was purified by flash-chromatography (SiO₂)using n-exane/ethyl acetate 60/40 as eluant, affording 1.2 g of3β-(2-hydroxyethylthio)-17β-(3-furyl)-5β-androstan-14β-ol as acolourless oil.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.70 (3H, s); 0.90 (3H, s); 2.72(2H, t); 2.74 (1H, dd); 3.22 (1H, bs); 3.70 (2H, t); 6.44 (1H, bs); 7.18(1H, bs); 7.30 (1H, bs).

To a solution of 0.90 g of3β-(2-hydroxyethylthio)-17β-(3-furyl)-5β-androstan-14β-ol, in 9 ml ofdry pyridine, 0.64 g of tosylchloride were added. After 5 hrs 10 ml ofwater and 50 ml of ethyl acetate were added. The organic phase waswashed with water, dried over anhydrous sodium sulfate to give 1.2 g of3β-(2-tosyioxyethylthio)-17β-(3-furyl)-5β-androstan-14.beta.-ol as acolourless oil.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.63 (3H, s); 0.90 (3H, s); 2.48(3H, s); 2.74 (1H, dd); 3.02-3.15 (2H, m); 4.15-4.20 (2H, m); 6.46 (1H,bs); 7.20 (1H, bs); 7.28-7.40 (5H, m).

To a solution of 0.21 g of 1-(2-hydroxyethyl)pyrrolidine in 5 ml ofdimethylformamide, 0.076 g of NaH (60% dispersion in mineral oil) wereadded and the mixture was kept at reflux for 2 hrs, then 0.35 g of3β-(2-tosyloxyethylthio)-17β-(3-furyl)-5β-androstan-14.beta.-ol in 2 mlof dimethylformamide was added, the mixture was kept at refluxtemperature for 4 hrs and 5 ml of water were added. The residue wasextracted with methylene chloride, the organic layer was washed withwater to neutral pH, dried over anhydrous sodium sulfate and evaporatedto dryness under reduced pressure. The crude product was purified byflash-chromatography (SiO₂) using methylene chloride/methanol 95/5 aseluant to give 0.22 g of the title compound (I-bz) as a white pastysolid.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.70 (3H, s); 0.90 (3H, s);1.72-1.82 (4H, m); 2.50-2.60 (6H, m); 2.67-2.75 (3H, m); 3.55-3.65 (4H,m); 6.44 (1H, bs); 7.18 (1H, bs); 7.30 (1H, bs).

EXAMPLE 52

3β-(2-(N-(2-(1-Pyrrolidinyl)ethyl)methylamino)ethylthio)-17β-(3-furyl)-5β-androstan-14β-ol(I-bz)

To a solution of 0.34 g of N-(2-(1-pyrrolidinyl)ethyl) methylamine in 5ml of dimethylformamide, 0.045 g of NaH (60% dispersion in mineral oil)were added under nitrogen and the mixture was stirred at roomtemperature for half an hr; a solution of 0.50 g of3β-(2-tosyloxyethylthio)-17β-(3-furyl)-5β-androstan-14.beta.-ol,prepared as described in Ex. 51, in 2 ml of dimethylformamide was added,the mixture was stirred for another 4 hrs and then 7 ml of water werepoured in. The residue was extracted with ethyl acetate, the organicsolution was washed with water to neutral pH, dried over anhydroussodium sulfate and evaporated to dryness under reduced pressure. Thecrude product was purified by flash-chromatography (SiO₂) usingmethylene chloride/methanol 95/5 as eluant to give 0.28 g of the titlecompound (I-ca)as an amorphous solid.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.70 (3H, s); 0.90 (3H, s);1.72-1.92 (4H, m); 2.50-2.60 (6H, m); 2.70-2.80 (3H, m); 3.50-3.65 (4H,m); 6.44 (1H, bs); 7.18 (1H, bs); 7.30 (1H, bs).

EXAMPLE 53

3β-(3-Dimethylaminopropylthio)-17β-(3-furyl)-5β-Androstan-14β-ol oxalate(I-ca)

The title compound (I-ca) (0.16 g) was obtained as a pale yellow solidfrom 3β-mercapto-17β-(3-furyl)-5β-androstan-14β-ol (II-d, Prep. 3)(0.20g) using the same procedure described in Ex. 47.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.72 (3H, s); 0.95 (3H, s); 2.22(9H, s); 2.36 (2H, t); 2.52 (2H, t); 2.73 (1H, dd); 3.22 (1H, bs); 6.48(1H, bs); 7.21 (1H, bs); 7.32 (1H, bs).

EXAMPLE 54

3β-(3-Aminopropylthio)-14β-methoxy-17β-(3-furyl)-5β-androstane oxalate(I-cb)

The title compound (I-cb) (0.11 g) was obtained as a white solid from3β-mercapto-14β-methoxy-17β-(3-furyl)-5β-androstane (prepared startingfrom 14β-methoxy-17β-(3-furyl)-5β-androstan-3β-ol (II-c, Prep.2)according to the sequence described in Prep. 1, Prep. 4 and Prep. 6)(0.23 g) using the same procedure described in Ex. 47.

1H-NMR (300 MHz, CD₃ OD, ppm from TMS): 0.77 (3H, s); 0.96 (3H, s); 2.61(2H, m); 3.31 (3H, s); 3.40 (1H, m); 6.35 (1H, bs); 7.19 (1H, bs); 7.33(1H, bs).

EXAMPLE 55

3β-(2-(1-Pyrrolidinyl)ethylthio)-14β-methoxy-17β-(3-furyl)-5β-androstanoxalate (I-cc)

The title compound (I-cc) (0.19 g) was obtained as a pale yellow solidfrom 0.25 g of 3β-mercapto-14β-methoxy-17β-(3-furyl)-5β-androstane(prepared starting from 14β-methoxy-17β-(3-furyl)-5β-androstan-3β-ol(II-c, Prep. 2) according to the

sequence described in Prep. 1, Prep. 4 and Prep. 6) using the sameprocedure described in Ex. 47.

¹ H-NMR (300 MHz, CD3OD, ppm from TMS): 0.78 (3H, s); 0.98 (3H, s); 2.60(2H, m); 3.31 (3H, s); 3.40 (1H, m); 6.37 (1H, bs); 7.19 (1H, bs); 7.32(1H, bs).

EXAMPLE 56

3β-(3-Aminoprgpylthio)-17β-(3-furyl)-androst-4-en-14β-ol oxalate (I-cd)

The title compound (I-cd) (0.15 g) was obtained as a white solid from0.20 g of 3β-mercapto-17β-(3-furyl)-androst-4-en-14β-ol (preparedstarting from 17β-(3-furyl)-androst-4-ene-3β,14β-diol, prepared asdescribed in Ex. 20, according to the sequence described in Prep. 1,Prep. 4 and Prep. 6) using the same procedure described in Ex. 47.

¹ H-NMR (300 MHz, CD3OD, ppm from TMS): 0.72 (3H, s); 1.08 (3H, s); 3.19(1H, m); 5.30 (1H, s); 6.45 (1H, bs); 7.23 (1H, bs); 7.33 (1H, bs).

EXAMPLE 57

3β-(2-(1-Pyrrolidinyl)ethylthio)-17β-(3-furyl)-androst-4-en-14.beta.-oloxalate (I-ce)

The title compound (I-ce)(0.18 g) was obtained as a white solid from0.22 g of 3β-mercapto-17β-(3-furyl)-androst-4-en-14β-ol (preparedstarting from 17β-(3-furyl)-androst-4-ene-3β,14β-diol, prepared asdescribed in Ex. 20, according to the sequence described in Prep. 1,Prep. 4 and Prep. 6) using the same procedure described in Ex. 47.

¹ H-NMR (300 MHz, CD3OD, ppm from TMS): 0.70 (3H, s); 1.08 (3H, s); 3.19(1H, m); 5.30 (1H, s); 6.46 (1H, bs); 7.20 (1H, bs); 7.31 (1H, bs).

EXAMPLE 58

3β-(3-Aminopropylthio)-17β-(3-furyl)-androst-5-en-14β-ol oxalate (I-cf)

The title compound (I-cf) (0.15 g) was obtained as a pale yellow pastysolid from 0.30 g of 3β-mercapto-17β-(3-furyl)-androst-5-en-14β-ol(prepared starting from 17β-(3-furyl)-androst-5-ene-3β,14β-diol,prepared as described in Ex. 22, according to the sequence described inPrep. 1, Prep. 4 and Prep. 6) using the same procedure described in Ex.47.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.72 (3H, s); 1.01 (3H, s); 2.63(2H, bt); 3.23 (2H, bs); 3.49 (1H, bm); 5.37 (1H, d); 6.47 (1H, bs);7.23 (1H, bs); 7.31 (1H, bs).

EXAMPLE 59

3β-(2-(1-Pyrrolidinyl)ethylthio)-17β-(3-furyl)-androst-5-en-14.beta.-oloxalate (I-cg)

The title compound (I-cg) (0.17 g) was obtained as a pale yellow solidfrom 0.25 g of 3β-mercapto-17β-(3-furyl)-androst-5-en-14β-ol (preparedstarting from 17β-(3-furyl)-androst-5-ene-3β,14β-diol, prepared asdescribed in Ex. 22, according to the sequence described in Prep. 1,Prep. 4 and Prep. 6) using the same procedure described in Ex. 47.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.71 (3H, s); 1.02 (3H, s); 2.63(2H, bt); 3.49 (1H, bm); 5.39 (1H, d); 6.47 (1H, bs); 7.21 (1H, bs);7.32 (1H, bs).

EXAMPLE 60

3β-(3-Aminopropylthio)-17β-(3-furyl)-5α-androstan-14 β-ol oxalate (I-ch)

The title compound (I-ch) (0.18 g) was obtained as a white solid from0.30 g of 3β-mercapto-17β-(3-furyl)-5α-androstan-14β-ol (preparedstarting from 17β-(3-furyl)-5α-androstan-14β-ol, prepared as describedin Ex. 24, according to the sequence described in Prep. 1, Prep. 4 andPrep. 6) using the same procedure described in Ex. 47.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.70 (3H, s); 0.79 (3H, s); 2.90(1H, m); 3.25 (3H, bs); 6.44 (1H, bs); 7.22 (1H, bs); 7.30 (1H, bs).

EXAMPLE 61

3β-(2-(1-Pyrrolidinyl)ethylthio)-17β-(3-furyl)-5α-androstan-14β-oloxalate (I-Ci)

The title compound (I-ci) (0.15 g) was obtained as a pale brown solidfrom 0.25 g of 3β-mercapto-17β-(3-furyl)-5α-androstan-14β-ol (preparedstarting from 17β-(3-furyl)-5α-androstan-14β-ol, prepared as describedin Ex. 24, according to the sequence described in Prep. 1, Prep. 4 andPrep. 6) using the same procedure described in Ex. 47.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.70 (3H, s); 0.79 (3H, s); 2.90(1H, m); 6.44 (1H, bs); 7.22 (1H, bs); 7.30 (1H, bs).

EXAMPLE 62

3β-(3-Aminopropylthio)-14β,15β-epoxy-17β-(3-furyl)-5.beta.-androstaneoxalate (I-cj)

The title compound (I-cj) (0.22 g) was obtained as a white pasty solidfrom 14β,15β-epoxy-17β-(3-furyl)-5β-androstane-3β-thiol (II-e, Prep. 4),(0.30 g) using the same procedure described in Ex. 47.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.75 (3H, s); 0.98 (3H, s); 2.28(1H, m); 2.65 (3H, bs); 3.30 (3H, bs); 3.47 (1H, s); 6.47 (1H, bs); 7.17(1H, bs); 7.27 (1H, bs).

EXAMPLE 63

3β-(2-(1-Pyrrolidinyl)ethylthio)-14β,15β-epoxy-17β-(3-furyl)-5β-androstaneoxalate (I-ck)

The title compound (I-ck) (0.24 g) was obtained as a white solid from14β,15β-epoxy-17β-(3-furyl)-5β-androstane-3β-thiol (II-e, Prep.4)(0.35g) using the same procedure described in Ex. 47.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.75 (3H, s); 0.98 (3H, s); 2.70(3H, m); 3.20 (3H, m); 3.48 (1H, s); 6.41 (lit, bs); 7.18 (1H, bs); 7.28(1H, bs).

EXAMPLE 64

3β-(3-Aminopropylthio), 14β,15β-epoxy-17β-(3-furyl)-androst-4-eneoxalate (I-cl)

The title compound (I-cl) (0.19 g) was obtained as a white solid from0.26 g of 14β,15β-epoxy-17β-(3-furyl)-androst-4-ene-3β-thiol (preparedstarting from 14β,15β-epoxy-17β-(3-furyl)-androst-4-en-3β-ol, preparedas described in Ex. 28, according to the sequence described in Prep. 1,Prep. 4 and Prep. 6) using the same procedure described in Ex. 47.

¹ H-NMR (300 MHz, CD3OD, ppm from TMS): 0.76 (3H, s); 1.02 (3H, s);2.66-2.71 (3H, m); 3.20 (1H, m); 3.41 (2H, bs); 3.59 (1H, s); 5.28 (1H,s); 6.40 (1H, bs); 7.17 (1H, bs); 7.29 (1H, bs).

EXAMPLE 65

3β-(2-(1-Pyrrolidinyl)ethylthio)-14β,15β-epoxy-17β-(3-furyl)-androst-4-eneoxalate (I-cm)

The title compound (I-cm) (0.21 g) was obtained as a pale brown solidfrom 0.25 g of 14β,15β-epoxy-17β-(3-furyl)-androst-4-ene-3β-thiol(prepared starting from 14β,15β-epoxy-17β-(3-furyl)-androst-4-en-3β-ol,prepared as described in Ex. 28, according to the sequence described inPrep. 1, Prep. 4 and Prep. 6) using the same procedure described in Ex.47.

¹ H-NMR (300 MHz, CD3OD, ppm from TMS): 0.76 (3H, s); 1.01 (3H, s);2.65-2.72 (3H, m); 3.20 (1H, m); 3.40 (2H, bs); 3.60 (1H, s); 5.28 (1H,s); 6.40 (1H, bs); 7.18 (1H, bs); 7.29 (1H, bs).

EXAMPLE 66

3β-(3-Aminopropylthio)-14β,15β-epoxy-17β-(3-furyl)-androst-5-ene oxalate(I-cn)

The title compound (I-cn) (0.20 g) was obtained as a pale yellow pastysolid from 0.25 g of 14β,15β-epoxy-17β-(3-furyl)-androst-5-ene-3β-thiol(prepared starting from 14β,15β-epoxy-17β-(3-furyl)-androst-5-en-3β-ol,prepared as described in Ex. 30, according to the sequence described inPrep. 1, Prep. 4 and Prep. 6) using the same procedure described in Ex.47.

¹ H-NMR (300 MHz, CD₃ OD, ppm from TMS): 0.74 (3H, s); 1.01 (3H, s);2.58 (2H, m); 2.72 (2H, d); 3.21 (2H, m); 3.47 (1H, m); 5.37 (1H, d);6.39 (1H, bs); 7.18 (1H, bs); 7.30 (1H, bs).

EXAMPLE 67

3β-(2-(1-Pyrrolidinyl)ethylthio)-14β,15β-epoxy-17β-3-furyl)-androst-5-ene oxalate (I,co)

The title compound (I-co) (0.28 g) was obtained as a white solid from0.30 g of 14β,15β-epoxy-17β-(3-furyl)-androst-5-ene-3β-thiol (preparedstarting from 14β,15β-epoxy-17β-(3-furyl)-androst-5-en-3β-ol (preparedas described in Ex. 30)according to the sequence described in Prep. 1,Prep. 4 and Prep. 6) using the same procedure described in Ex. 47.

¹ H-NMR (300 MHz., CD₃ OD, ppm from TMS): 0.76 (3H, s); 1.01 (3H, s);2.60 (2H, m); 2.70 (2H, d); 3.22 (2H, m); 3.48 (1H, m); 5.40 (1H, d);6.39 (1H, bs); 7.19 (1H, bs); 7.30 (1H, bs).

EXAMPLE 68

3β-(3-Aminopropylthio)-14,β,15β-epoxy-17β-(3-furyl)-5.alpha.-androstaneoxalate (I,cp)

The title compound (I-ep) (0.23 g) was obtained as a white solid from0.32 g of 14β,15β-epoxy-17β-(3-furyl)-5α-androstane- 3β-thiol (preparedstarting from 14β,15β-epoxy-17β-(3-furyl)-5α-androstan-3β-ol, preparedas described in Ex. 32, according to the sequence described in Prep. 1,Prep. 4 and Prep. 6) using the same procedure described in Ex. 47.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.74 (3H, s); 0.81 (3H, s); 2.87(1H, m); 2.68 (3H, m); 3.19 (3H, m); 3.47 (1H, s); 6.39 (1H, bs); 7.16(1H, bs); 7.28 (1H, bs).

EXAMPLE 69

3β-(2-(1-Pyrrolidinyl)ethylthio)-14β,15β-epoxy-17β-(3-furyl)-5α-androstaneoxalate (I-cq)

The title compound (I-eq) (0.21 g) was obtained as a pale yellowamorphous solid from 0.25 g of14β,15β-epoxy-17β-(3-furyl)-5α-androstane-3β-thiol (prepared startingfrom 14β,15β-epoxy-17β-(3-furyl)-5α-androstan-3β-ol, prepared asdescribed in Ex. 32, according to the sequence described in Prep. 1,Prep. 4 and Prep. 6) using the same procedure described in Ex. 47.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.73 (3H, s); 0.82 (3H, s); 2.90(1H, m); 2.67 (3H, m); 3.20 (3H, m); 3.47 (1H, s); 6.39 (1H, bs); 7.18(1H, bs); 7.26 (1H, bs).

EXAMPLE 70

3β-(3-Aminopropylthio)-17β-(3-furyl)-androst-4-ene oxalate (I-cr)

The title compound (I-cr) (0.18 g) was obtained as a white solid from0.24 g of 17β-(3-furyl)-androst-4-ene-3β-thiol (prepared starting from17β-(3-furyl)-androst-4-en-3β-ol, prepared as described in Ex. 37,according to the sequence described in Prep. 1, Prep. 4 and Prep. 6)using the same procedure described in Ex. 47.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.50 (3H, s); 1.03 (3H, s); 2.64(2H, bs); 3.16 (2H, m); 3.25 (2H, m); 5.29 (1H, s); 6.31 (1H, bs); 7.18(1H, bs); 7.40 (1H, bs).

EXAMPLE 71

3β-(2-(1-Pyrrolidinyl)ethylthio)-17β-(3-furyl)-androst-4-ene, oxalate(I-cs)

The title compound (I-cs) (0.15 g) was obtained as a white solid from0.20 g of 17β-(3-furyl)-androst-4-ene-3β-thiol (prepared starting from17β-(3-furyl)-androst-4-en-3β-ol, prepared as described in Ex. 37,according to the sequence described in Prep. 1, Prep. 4 and Prep. 6)using the same procedure described in Ex. 47.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.51 (3H, s); 1.02 (3H, s); 2.64(2H, bs); 3.16 (2H, m); 3.25 (2H, m); 5.30 (1H, s); 6.30 (1H, bs); 7.18(1H, bs); 7.42 (1H, bs).

EXAMPLE 72

3β-(3-Aminopropylthio)-17β-(3-furyl)-androst-5-ene oxalate (I-ct)

The title compound (I-ct) (0.24 g) was obtained as a pale yellow solidfrom 0.27 g of 17β-(3-furyl)-androst-5-ene-3β-thiol (prepared startingfrom 17β-(3-furyl)-androst-5-en-3β-ol, prepared as described in Ex. 39,according to the sequence described in Prep. 1, Prep. 4 and Prep. 6)using the same procedure described in Ex. 47.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.53 (3H, s); 0.98 (3H, s); 2.68(2H, m); 3.20 (2H, m); 3.46 (1H, m); 6.28 (1H, bs); 7.21 (1H, bs); 7.35(1H, bs).

EXAMPLE 73

3β-(2-(1-Pyrrolidinyl)ethylthio)-17β-(3-furyl)-androst-5-ene oxalate(I-cu)

The title compound (I-cu) (0.10-g) was obtained as a white solid from0.10 g of 17β-(3-furyl)-androst-5-ene-3β-thiol (prepared starting from17β-(3-furyl)-androst-5-en-3β-ol, prepared as described in Ex. 39,according to the sequence described in Prep. 1, Prep. 4 and Prep. 6)using the same procedure described in Ex. 47.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.52 (3H, s); 0.97 (3H, s); 2.68(2H, m); 3.22 (2H, m); 3.45 (1H, m); 6.28 (1H, bs); 7.21 (1H, bs); 7.34(1H, bs).

EXAMPLE 74

3β-(3-Aminopropylthio)-17β-(3-furyl)-androstane oxalate (I-cv)

The title compound (I-cv) (0.12 g) was obtained as a white pasty solidfrom 0.26 g of 17β-(3-furyl)-androstane-3β-thiol (prepared starting from17β-(3-furyl)-androstan-3β-ol, prepared as described in Ex. 41,according to the sequence described in Prep. 1, Prep. 4 and Prep. 6)using the same procedure described in Ex. 47.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.51 (3H, s); 0.73 (3H, s); 2.65(2H, bs); 3.710 (1H, m); 3.28 (2H, m); 6.29 (1H, bs); 7.20 (1H, bs);7.36 (1H, bs).

EXAMPLE 75

3β-(2-(1-Pyrrolidinyl)ethylthio)-17β-(3-furyl)-androstane oxalate (I-cw)

The title compound (I-cw) (0.15 g) was obtained as a pale brown solidfrom 0.25 g of 17β-(3-furyl)-androstane-3β-thiol (prepared starting from17β-(3-furyl)-androstan-3β-ol, prepared as described in Ex. 41,according to the sequence described in Prep. 1, Prep. 4 and Prep. 6)using the same procedure described in Ex. 47.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.53 (3H, s); 0.71 (3H, s); 2.67(2H, bs); 3.11 (1H, m); 3.26 (2H, m); 6.30 (1H, bs); 7.21 (1H, bs); 7.36(1H, bs).

EXAMPLE 76

3β-(2-(3-Aminopropoxy)ethoxy)-17β-(3-furyl)-5β-androstan-14.beta.-ol(I-cx)

The title compound (I-cx) (0.52 g) was obtained as a pale yellow solidfrom 2 g of 3β-(2-hydroxyethoxy)-17β-(3-furyl)-5β-andostran- 14β-ol,prepared as an intermediate in Ex.1, using the same procedure describedin Ex. 2.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.72 (3H, s); 0.92 (3H, s);2.70-2.79 (3H, m); 3.49-3.62 (6H, m); 3.65 (1H, bs); 6.47 (1H, bs); 7.21(1H, bs); 7.32 (1H, bs).

EXAMPLE 77

3β-(2-(3-Amino-2-hydroxypropoxy)ethoxy)-17β-(3,furyl)-5β-androstan-14β-ol (I-cy)

To a solution of 1.7 g of3β-(2-(2,3-dihydroxypropoxy)ethoxy)-17β-(3-furyl)-5β-androstan-14β-ol,prepared from 3γ-(2-hydroxyethoxy)-17β-(3-furyl)-5β-andostran-14β-ol,prepared as an intermediate in Ex.1, according to the sequence describedin Ex. 2 and Ex. 15, in 13 ml of dry pyridine, 0.80 g of tosyl chloridewere added at a temperature of 0° C. After 5 hrs 60 ml of water and 250ml of ethyl acetate were added, the organic layer was washed with water,dried over anhydrous sodium sulfate and evaporated to dryness underreduced pressure. The crude product was purified by flash-chromatography(SiO₂)using n-hexane/ethyl acetate 70/30 as eluant to give 2 g of 3β-(2-(3-tosyloxy-2-hydroxypropoxy)ethoxy)-17β-(3-furyl)-5β-androstan-14β-olas a white solid.

¹ H NMR (300 MHz, CDCl₃, ppm from TMS): 0.72 (3H, s); 0.92 (3H, s); 2.45(3H, s); 2.74 (1H, dd); 3.37-3.66 (7H, m); 3.91-4.00 (1H, m); 4.03-4.13(2H, m); 6.47 (1H, bs); 7.20 (1H, bs); 7.30 (1H, bs); 7.35 (d, 2H); 7.82(d, 2H).

To a solution of 2 g of3β-(2-(3-tosyloxy-2-hydroxypropoxy)ethoxy)-17β-(3-furyl)-5β-androstan-14β-ol,in 15 ml of dimethylsulfoxide, 2.14 g of sodium azide were added at roomtemperature. The solution was kept at reflux for 3 hrs, then 30 ml ofwater were added and the residue was extracted with methylene chloride.The organic layer was washed with water, dried over anhydrous sodiumsulfate and evaporated to dryness under reduced pressure. The crudeproduct was purified by flash-chromatography (SiO₂) using n-hexane/ethylacetate 80/20 as eluant to give 1.4 g of3β-(3-azido-2-hydroxypropoxy)-17β-(3-furyl)-5β-androstan-14β-ol.

¹ H NMR (300 MH_(z), CDCl₃, ppm from TMS): 0.72 (3H, s); 0.92 (3H, s);2.74 (1H, m); 3.37-3.66 (9H, m); 3.71-3.80 (1H, m); 6.47 (1H, bs); 7.21(1H, bs); 7.32 (1H, bs).

A solution of 1 g of3β-(3-azido-2-hydroxypropoxy)-17β-(3-furyl)-5β-androstan-14β-ol in 20 mlof diethyl ether is added to a suspension of 0.50 g of lithium aluminiumhydride in 18 ml of diethyl ether. The mixture was kept at reflux for 12hrs, then were added 0.5 ml of water, 0.5 ml of sodium hydroxyde (watersolution 10%) and 1.9 ml of water. The mixture was filtered over acelite cake, the organic solution was washed with water, dried oversodium sulfate and evaporated to dryness under reduced pressure. Thecrude residue was purified by flash-chromatography (SiO₂) usingmethylene chloride/methanol/30% ammonia solution 90/10/1 as eluant togive 0.65 g of the title compound (I-cy) as a light yellow solid.

¹ H NMR (300 MH_(z), CDCl₃, ppm from TMS): 0.72 (3H, s); 0.92 (3H, s);2.74 (1H, m); 3.37-3.66 (9H, m); 3.71-3.80 (1H, m); 6.47 (1H, bs); 7.22(1H, bs); 7.32 (1H, bs).

EXAMPLE 78

3β-(2-(2,3-Diaminopropoxy)ethoxy)-17β-(3-furyl)-5β-androstan-14β-ol(I-cz)

The title compound (I-cz) (0.62 g) was obtained as a white solid from1.5 g of3β-(2-(2,3-ditosyloxypropoxy)ethoxy)-17β-(3-furyl)-5β-androstan-14β-olprepared from 3β-(2-hydroxyethoxy)-17β(3-furyl)-5β-andostran-14β-ol,prepared as an intermediate in Ex.1, according to the sequence describedin Ex. 2 and Ex. 15.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.72 (3H, s); 0.92 (3H, s);2.59-2.68 (1H, m); 2.71-2.86 (2H, m); 2.90-2.99 (1H, m); 3.37-3.67 (7H,m); 6.47 (1H, bs); 7.21 (1H, bs); 7.32 (1H, bs).

EXAMPLE 79

3β(2-(3-(1-Pyrrolidinyl)propoxy)ethoxy)-17β-(3-furyl)-5β-androstan-14β-ol (I-da)

The title compound (I-da) (1.5 g) was obtained as a colourless oil from3β-(2-tosyloxyethoxy)-17β-(3-furyl)-5β-androstan-14β-ol (2.1 g),prepared as described in Ex. 7, using the same procedure described inEx. 8.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.72 (3H, s); 0.92 (3H, s);2.51-2.61 (4H, m); 2.62-2.68 (2H, m); 2.74 (1H, m); 3.49-3.62 (6H, m);3.65 (1H, bs); 6.47 (1H, bs); 7.22 (1H, bs); 7.32 (1H, bs).

EXAMPLE 80

3β-(2-(3-(1-Pyrrolidinyl)propylamino)ethoxy)-17β-(3-furyl)-5.beta.-androstan-14β-ol(I-db)

The title compound (I-db) (0.50 g) was obtained as a colourless oil from3β-(2-tosyloxyethoxy)-17β-(3-furyl)-5β-androstan-14β5-ol (0.62 g),prepared as described in Ex. 7, using the same procedure described inEx. 7.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.72 (3H, s); 0.92 (3H, s);2.51-2.61 (4H, m); 2.62-2.68 (2H, m); 2.71-2.85 (5H, m); 3.46-3.57 (2H,m); 3.63 (1H, bs); 6.47 (1H, bs); 7.22 (1H, bs); 7.32 (1H, bs).

PREPARATION OF INTERMEDIATES Preparation 1

17β-(3-Furyl)-14β,15β-epoxy-5β-androstan-3α-ol (II-b)

To a solution of 5.0 g of 14β,15β-epoxy-17β-(3-furyl)-5β-androstan-3β-ol(E. Yoshii et al., Chem. Pharm. Bull., 1976, 24, 3216) in 70 ml ofmethylene chloride, 2.5 g of 4-methylmorpholine N-oxide, 0.25 g oftetrapropylammonium perruthenate and 4.0 g of powdered 4A molecularsieves were added at room temperature. After 4 hrs the solvent wasevaporated to dryness under reduced pressure and the crude productpurified by flash-chromatography (SiO₂) using n-hexane/ethyl acetate70/30 as eluant to give 7.9 g of14β,15β-epoxy-17β-(3-furyl)-5β-androstan-3-one as a white solid.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.76 (3H, s); 1.03 (3H, s); 2.65(1H, d); 3.62 (1H, s); 6.50 (1H, bs); 7.18 (1H, bs); 7.29 (1H, bs).

To a solution of 4.5 g of 14β,15β-epoxy-17β-(3-furyl)-5β-androstan-3-onein 30 ml of dry tetrahydrofuran at-78° C, a solution of 9.8 g oftri-tert-butoxyaluminum-hydride in tetrahydrofuran was added dropwise.The mixture was stirred for 20 hrs, then 40 ml of water were added andthe temperature raised to 25° C. The aluminum salts were filtered on acelite cake and washed with methanol. The solution was concentratedunder reduced pressure and extracted with methylene chloride. Theorganic layer was dried over sodium sulfate and evaporated to drynessunder reduced pressure to give 4.3 g of the title compound (II-b) as awhite solid.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.74 (3H, s); 1.00 (3H, s); 2.65(1H, d); 3.51 (1H, s); 3.65 (1H, m); 6.48 (1H, bs); 7.18 (1H, bs); 7.29(1H, bs).

Preparation 2

14β-Methoxy-17β-(3-furyl)-5β-androstan-3β-ol (II-c)

To a solution of 10 g of 17β-(3-furyl)-5β-androstane-3β,14β-diol (II-a:Ref. comp.) (Minato H. and Nagasaki T., J. Chem. Soc. (C), 1966, 377)in80 ml of dimethylformamide, 18 g of imidazole and 20.0 g oft-butyldimethylsilyl chloride were added at 0° C. After 12 hrs themixture was poured into water and extracted with ethyl acetate. Theorganic layer was dried over sodium sulfate and evaporated to drynessunder reduced pressure and 15 g of crude3β-tert-butyldimethylsilyloxy-17β-(3-furyl)-5β-androstan-14β-ol wereobtained. A suspension of this protected alcohol and 1.3 g of KH in 75ml of tetrahydrofuran was heated at 70° C. for an hr; then 2.7 g ofmethyl iodide were added. After 30' the mixture was poured into waterand extracted with ethyl acetate. The organic layer was dried oversodium sulfate and evaporated to dryness under reduced pressure to give12 g of3β-tert-butyldimethylsilyloxy-14β-methoxy-17β-(3-furyl)-5.beta.-androstaneas a white amorphous solid.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.080 (6H, s); 0.81 (3H, s);0.93 (9H, s); 0.98 (3H, s); 2.13-2.30 (1H, m); 2.70 (1H, m); 3.38 (3H,s); 4.07 (1H, bs); 6.41 (1H, bs); 7.18 (1H, bs); 7.33 (1H, bs).

A solution of 3.0 g of3β-tert-butyldimethylsilyloxy-14β-methoxy-17β-(3-furyl)-5.beta.-androstanein 57 ml of a 1.0 M solution of tetrabutylammonium fluoride was heatedat 70° C. under nitrogen for an hr and then poured into a saturatedsolution of sodium chloride. The mixture was extracted with ethylacetate and the organic layer was dried over sodium sulfate, evaporatedto dryness under reduced pressure and purified by flash-chromatography(SiO₂) using n-hexane/ethyl acetate 80/20 as eluant to give 2.0 g of thetitle compound (II-c) as a white solid.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.78 (3H, s); 1.00 (3H, s);2.15-2.30 (1H, m); 2.70 (1H, m); 3.40 (3H, s); 4.18 (1H, bs); 6.39 (1H,bs); 7.18 (1H, bs); 7.32 (1H, bs).

Preparation 3

3β-Mercapto-17β-(3-furyl)-5β-androstan-14β-ol (II-d)

To a solution of 1.5 g of3β-acetylthio-17β-(3-furyl)-5β-androstan-14β-ol (VI-a, Prep. 5)in 20 mlof methanol, hydrogen was bubbled for 15', the solution was saturatedwith gaseous ammonia and kept on standing for 3 hrs at room temperature.The mixture was evaporated to dryness under reduced pressure andpurified by flash-chromatography (SiO₂) using n-hexane/ethyl acetate95/5 as eluant to give 1.2 g of the title compound (II-d) as a whitesolid.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.72 (3H, s); 0.98 (3H, s);2.17-2.31 (2H, m); 2.76 (1H, dd); 3.62 (1H, bs); 6.48 (1H, bs); 7.22(1H, bs); 7.33 (1H, bs).

Preparation 4

14β,15β-Epoxy17β-(3-furyl)-5β-androstane-3β-thiol (II-e)

To a solution of 1.6 g of3β-acetylthio-14β,15β-epoxy-17β-(3-furyl)-5β-androstane (VI-b, Prep.6)in 20 ml of methanol, hydrogen was bubbled for 15', the solution wassaturated with gaseous ammonia and kept on standing for 3 hrs at roomtemperature. The mixture was evaporated to dryness under reducedpressure and purified by flash-chromatography (SiO₂) usingn-hexane/ethyl acetate 95/5 as eluant to give 1.3 g of the titlecompound (II-e) as a white solid.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.76 (3H, s); 1.02 (3H, s); 2.65(1H, d); 3.51 (1H, s); 3.63 (1H, bs); 6.48 (1H, bs); 7.18 (1H, bs); 7.29(1H, bs).

Preparation 5

3β-Acetylthio-17β-(3-furyl)-5β-androstan-14β-ol (VI-a)

Diisopropyl azodicarboxylate (3.6 ml) was added to a solution of 4.7 gof triphenylphosphine in 90 ml of tetrahydrofuran at 0° C. and themixture was stirred for 30'. To this mixture a solution of 2.2 g of17β-(3-furyl)-5β-androstane-3α,14β-diol (Humber D. and al., Steroids,1983, 42, 189) and 2.2 ml of thiolacetic acid in 90 ml oftetrahydrofuran was added dropwise and the residue was stirred for an hrat room temperature. The solvent was evaporated to dryness under reducedpressure and the crude product was purified by flash-chromatography(SiO₂) using n-hexane/ethyl acetate 95/5 as chant to give 1.6 g of thetitle compound (Vl-a) as a white solid.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.72 (3H, s); 0.96 (3H, s); 2.31(3H, s); 2.77 (1H, dd); 4.08 (1H, bs); 6.48 (1H, bs); 7.21 (1H, bs);7.32 (1H, bs).

Preparation 6

3β-Acetylthio-14β,15β-epoxy-17β-(3-furyl)-5β-androstane (VI,b)

Diisopropyl azodicarboxylate (3.5 ml) was added to a solution of 4.5 gof triphenylphosphine in 85 ml of tetrahydrofuran at 0° C. and themixture was stirred for 30'. To this mixture a solution of 2.0 g of14β,15β-epoxy-17β-(3-furyl)-5β-androstan-3α-ol and 2.05 ml ofthiolacetic acid in 90 ml of tetrahydrofuran was added dropwise and theresulting mixture was stirred for an hr at room temperature. The solventwas evaporated to dryness under reduced pressure and the crude productwas purified by flash-chromatography (SiO₂) using n-hexane/ethyl acetate95/5 as eluant to give 1.7 g of the title compound (VI-b) as a whitesolid.

¹ H-NMR (300 MHz, CDCl₃, ppm from TMS): 0.73 (3H, s); 1.00 (3H, s); 2.32(3H, s); 2.65 (1H, d); 3.50 (1H, s); 4.10 (1H, bs); 6.48 (1H, bs); 7.18(1H, bs); 7.29 (1H, bs).

We claim:
 1. Cyclopentanperhydrophenanthren-17β-(3-furyl)-3-derivativesof formula (I) ##STR7## wherein: X is O or S;the symbol means that thesubstituents in positions 3, 5, 14, and 15 can have an α or βconfiguration, with the proviso that when X═S only the 3β configurationis present; the symbol --- means that single or double bonds can bepresent; R is C2-C6 alkyl or C3-C6 alkenyl, substituted independently bya quaternary ammonium group or one or more OR3, SR3, NR4R5, C(NH)NR6R7,with the proviso that when X is oxygen and R1 is βOH and R2 is H and theconfiguration in position 5is β and C2-C6 alkyl is ethyl or n-propyl,NR4R5 is not dimethylamino; R1 is H or hydroxy or methoxy or O(CH₂)_(n)NR8R9; wherein n is 2 or 3; R2 is H; R3 is C2-C4 alkyl substituted byone or more NR6R7 or by NR6R7 and OH; R4, R5 are independently H,methyl, C2-C6 alkyl or C3-C6 alkenyl unsubstituted or substituted or byone or more NR6R7, or NR6R7 and OH, or R4 is hydrogen and R5 isC(NH)NH2; R6, R7 are independently H, C1-C4 alkyl; R8, R9 areindependently H, methyl, ethyl and the pharmaceutically acceptable saltsthereof.
 2. A compound according to claim 1, which is selectedfrom:3β-(2-Trimethylammonium-ethoxy)-17β-(3-furyl)-5β-androstan-14β-olchloride 3β-(2-Aminoethoxy)-17β-(3-furyl)-5β-androstan-14β-ol3β-(3-Aminopropoxy)-17β-(3-furyl)-5β-androstan-14β-ol3β-(4-Aminobutoxy)-17β-(3-furyl)-5β-androstan-14β-ol β-(4-Aminobut-(2-en)oxy)-17β-(3-furyl)-5β-androstan-14.beta.-ol3β-(4-Aminobut-(2-yn)oxy)-17β-(3-furyl)-5β-androstan-14.beta.-ol3β-(2-Methylaminoethoxy)-17β-(3-furyl)-5β-androstan-14β-ol3β-(2-(2-Amidino)ethoxy)-17β-(3-furyl)-5β-androstan-14β-ol3β-(2-(2-Aminoethoxy)ethoxy)-17β-(3-furyl)-5β-androstan-14.beta.-ol3β-(2-(3-Aminopropoxy)ethoxy)-17β-(3-furyl)-5β-androstan-14.beta.-ol β-(2-(3-Dimethylaminopropoxy)ethoxy)-17β-(3-furyl)-5β-androstan-14β-ol3β(2-(3-Dimethylaminopropylthio)ethoxy)-17α-(3-furyl)-5β-androstan-14β-ol3β-(2-(3-Dimethylaminopropylamino)ethoxy)-17β-(3-furyl)-5β-androstan-14β-ol3β-(2-(3-Amino-2-hydroxypropoxy)ethoxy)-17β-(3-furyl)-5β-androstan-14β-ol3β-(2-(2,3-Diaminopropoxy)ethoxy)-17β-(3-furyl)-5β-androstan-14β-ol3β-(2-Guanidinoethoxy)-17β-(3-furyl)-5β-androstan-14β-o3β-(3-Guanidinopropoxy)-17β-(3-furyl)-5β-androstan-14β-ol3β-(4-Guanidinobutoxy)-17β-(3-furyl)-5β-androstan-14β-ol3β-(2,3-Diaminopropoxy)-17β-(3-furyl)-5β-androstan-14β-ol3β-(3-(3-Amino-2-hydroxypropoxy)propoxy)-17β-(3-furyl)-5β-androstan-14β-ol3β-(3-(3-Amino-2-hydroxypropylamino)propoxy)-17β-(3-furyl)-5.beta.-androstan-14β-olβ -(3-Aminopropoxy)-14β-methoxy-17β-(3-furyl)-5β-androstane3β-(3-Aminopropoxy)-17β-(3-furyl)-androst-4-en-14β-ol3β-(3-Aminopropoxy)-17β-(3-furyl)-androst-5-en-14β-ol3β-(3-Aminopropoxy)-17β-(3-furyl)-5α-androstan-14β-ol β-(3-Aminopropoxy)-17β-(3-furyl)-5β-androstan-14α-ol3β-(3-Aminopropoxy)-14β,15β-epoxy-17β-(3-furyl)-5β-androstane3β-(3-Aminopropoxy)-14β,15β-epoxy-17β-(3-furyl)-androst-4-ene3β-(3-Aminopropoxy)-14β,15β-epoxy-17β-(3-furyl)-androst-5-ene β-(3-Aminopropoxy)-14β,15β-epoxy-17β-(3-furyl)-5.alpha.-androstane3β-(3-Aminopropoxy)-14α,15α-epoxy-17β-(3-furyl)-5.beta.-androstane3β-(3-Aminopropoxy)-17β-(3-furyl)-5β,14β-androstane3β-(3-Aminopropoxy)-17β-(3-furyl)-androst-4-ene β-(3-Aminopropoxy)-17β-(3-furyl)-androst-5-ene3β-(3-Aminopropoxy)-17β-(3-furyl)-5α-androstane3β-(3-Aminopropoxy)-17β-(3-furyl)-5α-androstane and the correspondingX═S derivatives and for X═O the corresponding 3α derivatives.
 3. Apharmaceutical composition for treatment of cardiovascular disorder orhypertension containing a compound of formula (I) of claim 1 or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier and/or diluent.
 4. A method for the treatment of apatient having cardiovascular disorder or hypertension, which comprisesadministering to the patient an effective amount of a compound offormula (I) of claim 1, or pharmaceutically acceptable salt thereof. 5.The method of claim 4 for the treatment of hypertension.
 6. The methodof claim 4 for the treatment of cardiac failure.